Clinical trial NCT04638517: The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
Official title: 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 type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pulmonary Fibrosis
Telomere Shortening
Telomere Disease
Dyskeratosis Congenita
Lead sponsor: The University of Queensland
Sponsor class: OTHER
First posted: 2020-11-20
Enrollment: 50
Sex: ALL
Minimum age (years): 5
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. Males and females aged \>5 years, able to take capsules orally.
2. 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.
3. Age-adjusted peripheral blood leukocyte telomere length \< 10th centile on Flow-FISH.
4. FVC \> 40% predicted.
5. DLCO \> 25% predicted.
6. If receiving background pirfenidone / nintedanib, stable dose for 28 days prior to screening.
7. Able to understand and sign a written informed consent form (or legally authorised representative).
8. 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:

1. Actively or imminently listed for lung transplantation.
2. Undergone, awaiting, or likely to require bone marrow transplantation within 12 months.
3. Concurrent enrolment in another study.
4. Females with a positive pregnancy test at screening or currently breastfeeding.
5. Pelvic infection.
6. Past jaundice with oral contraceptives.
7. Undiagnosed abnormal genital bleeding.
8. Undiagnosed ovarian/uterine masses
9. Any history of malignancy likely to result in significant disability or likely to require significant medical or surgical intervention within the next 12 months.
10. History of androgen-dependent tumour.
11. 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.
12. History of end-stage liver disease or ALT or AST \> 3 times the upper limit of normal.
13. History of end-stage kidney disease requiring dialysis.
14. Markedly impaired cardiac function.
15. Known increased risk of or history of thromboembolism (e.g. Factor V Leiden, Protein C or S deficiency).
16. Uncontrolled hypertension.
17. Uncontrolled lipoprotein disorder.
18. Poorly-controlled diabetes mellitus.
19. History of marked or persistent androgenic reaction to previous gonadal steroid therapy.
20. History of epilepsy induced or worsened by previous gonadal steroid therapy.
21. History of raised intracranial pressure.
22. Known intolerance to danazol.
23. Porphyria.
24. 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.
25. Professional singer due to potential for voice change.
26. Competitive athletes.
27. Prostate specific antigen (PSA) above the upper limit of normal (adult males only).

Primary outcomes:
measure: Change in absolute telomere length from baseline (base pairs)
timeFrame: 12 months
Secondary outcomes:
measure: Number of participants with treatment-emergent adverse events
timeFrame: 12 months
measure: Number of Participants With Death or Non-Elective Hospitalisation
timeFrame: 12 months
measure: Change in telomere length from baseline to 3, 6 and 9 months (base pairs)
timeFrame: 3, 6 and 9 months
measure: Change in forced vital capacity (FVC) at 6 and 12 months
timeFrame: 6 and 12 months
measure: Change in diffusing capacity for carbon monoxide at 6 and 12 months
timeFrame: 6 and 12 months
measure: Change in 6-minute walk distance from baseline
timeFrame: 12 months
measure: Change in Leicester cough questionnaire (LCQ) from baseline
timeFrame: 12 months
measure: Change in King's Brief Interstitial Lung Disease Questionnaire (K-BILD) from baseline
timeFrame: 12 months
measure: Change in Parent cough-specific quality of life (PCSQoL) from baseline
timeFrame: 12 months
Other outcomes:
Locations:
city: Newcastle
country: Australia
facility: John Hunter Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: Sydney
country: Australia
facility: Royal Prince Alfred Hospital
state: New South Wales
city: Sydney
country: Australia
facility: The Children's Hospital Westmead
state: New South Wales
city: Brisbane
country: Australia
facility: The Prince Charles Hospital
state: Queensland
city: Adelaide
country: Australia
facility: Royal Adelaide Hospital
state: South Australia
city: Melbourne
country: Australia
facility: The Alfred
state: Victoria
city: Melbourne
country: Australia
facility: The Austin
state: Victoria
city: Perth
country: Australia
facility: Fiona Stanley Hospital
state: Western Australia
Study officials:
References:
citation: Mackintosh JA, Pietsch M, Lutzky V, Enever D, Bancroft S, Apte SH, Tan M, Yerkovich ST, Dickinson JL, Pickett HA, Selvadurai H, Grainge C, Goh NS, Hopkins P, Glaspole I, Reynolds PN, Wrobel J, Jaffe A, Corte TJ, Chambers DC. TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis. BMJ Open Respir Res. 2021 Dec;8(1):e001127. doi: 10.1136/bmjresp-2021-001127.