The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis

Study Overview
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Brief Summary
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TELO-SCOPE is a national, multi-centre, double-blind, placebo-controlled, randomised (2:1) trial which will test the hypothesis that, compared to placebo, the addition of danazol to standard of care in pulmonary fibrosis associated with short telomeres is safe and will result in reduced telomere attrition.

Detailed Description
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TELO-SCOPE is a national, multi-centre, double-blind, placebo-controlled, randomised trial which will be conducted in subjects aged >5 years with a multi-disciplinary diagnosis of pulmonary fibrosis and with age-adjusted telomere length below the 10th centile in adults; and for children (age < 16 years), a confirmed diagnosis of Dyskeratosis Congenita (DC). Consenting participants who meet all other inclusions and no exclusions will be randomised (n=50, 2:1 (danazol:placebo)) to receive danazol (maximum tolerated dose (up to 800mg daily, two-divided doses) or matched placebo, for 12 months in addition to standard of care background therapy. The primary outcome is change in telomere length at 12 months.

Official Title
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The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis

Conditions
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Pulmonary Fibrosis, Telomere Shortening, Telomere Disease, Dyskeratosis Congenita

Intervention / Treatment
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* Drug: Danazol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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. Professional singer due to potential for voice change. Competitive athletes. Prostate specific antigen (PSA) above the upper limit of normal (adult males only).

Ages Eligible for Study
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Minimum Age: 5 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Danazol<br>800mg daily in two divided doses orally for 12 months. In subjects who have difficulty tolerating danazol / placebo, the dose will be reduced by 200mg/day and side effects will be reassessed. If symptoms related to the study drug persist, subsequent 200mg/day dose reductions will be allowed until a tolerated dose is achieved. Background antifibrotic therapy is allowed. | Drug: Danazol<br>* Danazol up to 800mg daily in two-divided doses.<br>|
| Placebo Comparator: Placebo<br>Matching placebo capsules. | Drug: Placebo<br>* Matching placebo.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in absolute telomere length from baseline (base pairs) | Telomere length will be measured in absolute terms (base pairs) using the telomere shortest length assay (TeSLA). | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with treatment-emergent adverse events |  | 12 months | 
| Number of Participants With Death or Non-Elective Hospitalisation |  | 12 months | 
| Change in telomere length from baseline to 3, 6 and 9 months (base pairs) |  | 3, 6 and 9 months | 
| Change in forced vital capacity (FVC) at 6 and 12 months | FVC is measured as the volume of air exhaled during spirometry. | 6 and 12 months | 
| Change in diffusing capacity for carbon monoxide at 6 and 12 months | DLCO is a measurement of the of the lung's gas transfer ability. | 6 and 12 months | 
| Change in 6-minute walk distance from baseline |  | 12 months | 
| Change in Leicester cough questionnaire (LCQ) from baseline |  | 12 months | 
| Change in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) from baseline |  | 12 months | 
| Change in Parent cough-specific quality of life (PCSQoL) from baseline |  | 12 months |