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Trial registered on ANZCTR


Registration number
ACTRN12620001363976p
Ethics application status
Submitted, not yet approved
Date submitted
26/10/2020
Date registered
18/12/2020
Date last updated
18/12/2020
Date data sharing statement initially provided
18/12/2020
Type of registration
Prospectively registered

Titles & IDs
Public 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?
Scientific 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?
Secondary ID [1] 302606 0
None
Universal Trial Number (UTN)
Trial acronym
TELO-SCOPE
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Pulmonary fibrosis associated with age adjusted telomere length less than the 10th centile. 319496 0
Condition category
Condition code
Respiratory 317459 317459 0 0
Other respiratory disorders / diseases

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
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.
Intervention code [1] 318892 0
Treatment: Drugs
Comparator / control treatment
Placebo (glucose capsule).
Control group
Placebo

Outcomes
Primary outcome [1] 325491 0
Change in telomere length (in base pairs) at 12 months measured using the telomere shortest length assay (TeSLA).
Timepoint [1] 325491 0
12 months after randomisation to danazol.
Secondary outcome [1] 388142 0
Number of participants with treatment-emergent adverse events. Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). The investigator or site staff will be responsible for detecting, documenting, and reporting events that meet the definition of an adverse event (AE) or serious adverse event (SAE).
Timepoint [1] 388142 0
From screening visit 1 to follow-up (30 days after IMP administration).
Secondary outcome [2] 388144 0
Number of participants with death or non-elective hospitalisation.
Timepoint [2] 388144 0
Assessed throughout study participation.
Secondary outcome [3] 388145 0
Change in telomere length (base pairs) using TeSLA from baseline to 3, 6 and 9 months.
Timepoint [3] 388145 0
Telomere length measurement from baseline (randomisation to danazol) to 3, 6 and 9 months.
Secondary outcome [4] 388146 0
Change in forced vital capacity (FVC) on spirometry.
Timepoint [4] 388146 0
Change from baseline (randomisation to danazol) to 6 and 12 months.
Secondary outcome [5] 388147 0
Change in diffusing capacity for carbon monoxide (DLCO) using Single-Breath technique..
Timepoint [5] 388147 0
Measured from baseline (randomisation to danazol) to 6 and 12 months.
Secondary outcome [6] 388148 0
Change in walk distance from baseline measured on six-minute walk test.
Timepoint [6] 388148 0
Measured from baseline (randomisation to danazol) to 12 months.
Secondary outcome [7] 388149 0
Change in cough measured using the Leicester Cough Questionnaire.
Timepoint [7] 388149 0
Measured from baseline (randomisation to danazol) to 12 months.
Secondary outcome [8] 389135 0
Change in cough measured using Parent Cough-Specific Quality of Life Questionnaire.
Timepoint [8] 389135 0
Measured from baseline (randomisation to danazol) to 12 months.
Secondary outcome [9] 389136 0
Change in quality of life measured using King's Brief Interstitial Lung Disease Questionnaire.
Timepoint [9] 389136 0
Measured from baseline (randomisation to danazol) to 12 months.

Eligibility
Key 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).
Minimum age
5 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key 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.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,WA,VIC
Recruitment hospital [1] 17876 0
The Prince Charles Hospital - Chermside
Recruitment hospital [2] 17877 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [3] 17878 0
John Hunter Hospital - New Lambton
Recruitment hospital [4] 17879 0
The Alfred - Melbourne
Recruitment hospital [5] 17880 0
Austin Health - Austin Hospital - Heidelberg
Recruitment hospital [6] 17881 0
Fiona Stanley Hospital - Murdoch
Recruitment hospital [7] 17882 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [8] 17883 0
Sydney Children's Hospital - Randwick
Recruitment hospital [9] 17884 0
The Children's Hospital at Westmead - Westmead
Recruitment postcode(s) [1] 31733 0
4032 - Chermside
Recruitment postcode(s) [2] 31734 0
2050 - Camperdown
Recruitment postcode(s) [3] 31735 0
2305 - New Lambton
Recruitment postcode(s) [4] 31736 0
3004 - Melbourne
Recruitment postcode(s) [5] 31737 0
3084 - Heidelberg
Recruitment postcode(s) [6] 31738 0
6150 - Murdoch
Recruitment postcode(s) [7] 31739 0
5000 - Adelaide
Recruitment postcode(s) [8] 31740 0
2031 - Randwick
Recruitment postcode(s) [9] 31741 0
2145 - Westmead

Funding & Sponsors
Funding source category [1] 307035 0
Government body
Name [1] 307035 0
Australian Government Department of Health, Medical Research Future Fund
Address [1] 307035 0
Department of Health
GPO Box 9848
Canberra ACT 2601
Australia
Country [1] 307035 0
Australia
Primary sponsor type
University
Name
The University of Queensland
Address
Faculty of Medicine
The University of Queensland
288 Herston Road
Herston Qld 4006 Australia
Country
Australia
Secondary sponsor category [1] 307605 0
None
Name [1] 307605 0
Address [1] 307605 0
Country [1] 307605 0

Ethics approval
Ethics application status
Submitted, not yet approved
Ethics committee name [1] 307165 0
Metro South Human Research Ethics Committee
Ethics committee address [1] 307165 0
Metro South Research
Level 7, Translational Research Institute
37 Kent Street
Woolloongabba QLD 4102
Ethics committee country [1] 307165 0
Australia
Date submitted for ethics approval [1] 307165 0
21/09/2020
Approval date [1] 307165 0
Ethics approval number [1] 307165 0

Summary
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.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106258 0
Prof Daniel Chambers
Address 106258 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 106258 0
Australia
Phone 106258 0
+61 731396904
Fax 106258 0
+61731396140
Email 106258 0
daniel.chambers@health.qld.gov.au
Contact person for public queries
Name 106259 0
Dr John Mackintosh
Address 106259 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 106259 0
Australia
Phone 106259 0
+61 731395695
Fax 106259 0
+61731396140
Email 106259 0
john.mackintosh@health.qld.gov.au
Contact person for scientific queries
Name 106260 0
Dr John Mackintosh
Address 106260 0
The Prince Charles Hospital
Rode Road
CHERMSIDE QLD 4032
Country 106260 0
Australia
Phone 106260 0
+61 731395695
Fax 106260 0
+61731396140
Email 106260 0
john.mackintosh@health.qld.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Study information will be de-identified before entering into the database and grouped data will be reported.
What supporting documents are/will be available?
No other documents available
Summary results
No Results