Evaluating Efficacy and Safety of Danazol in Severe Hematologic or Pulmonary Disease Related to Telomeropathy

Telomere Shortening Clinical Trial

— ANDROTELO  

Official title:

Essai Bayésien de Phase I/II évaluant l'efficacité et la tolérance du Danazol Chez Les Patients Ayant Une Atteinte hématologique ou Pulmonaire sévère liée à Une téloméropathie - ANDROTELO

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT03710356
• Other study ID #: P170925J
• Secondary ID: 2018-001686-17
• Status: Not yet recruiting
• Phase: Phase 1/Phase 2
• Start date: October 20, 2018
• Est. completion date: October 20, 2022

Study information

• Verified date: October 2018
• Source: Assistance Publique - Hôpitaux de Paris
• Contact: Flore SICRE DE FONTBRUNE, MD PhD
• Phone: 142494949
• Email: flore.sicre-de-fontbrune[@]aphp.fr
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Constitutional mutations of genes involved in telomere repair and maintenance are responsible for "telomeropathy" (" Congenital Dyskeratosis "). Attrition of telomeres promotes cell senescence and genetic instability. The penetrance and severity of organ damage (pulmonary, hematological, liver, and neurological) is variable, depending on the gene involved, the generation concerned (anticipation phenomenon) and also environmental factors.

In cases of bone marrow failure, the only curative treatment is hematopoietic stem cell transplant, often limited by pulmonary and / or hepatic involvement or the absence of a suitable HLA match donor. The pulmonary phenotype is most often that of idiopathic pulmonary fibrosis. In severe forms, a lung transplant is proposed in the absence of contraindications. Anti-fibrotic treatments are not very effective or not evaluated. The observed decrease in the vital capacity of these patients is 300 ml / year, abnormally high compared to idiopathic forms. Evolution without transplant is in both situations rapidly unfavorable; the prognosis after lung or marrow transplant is also worse than that of similar transplants without telomeres disease.

Danazol has been used for over 4 decades in acquired and constitutional bone marrow failure in the absence of a therapeutic alternative. In telomeropathy, retrospective data on small cohorts indicate a haematological response rate of 60-70%. A prospective study in the United States recently showed a haematological response at 1 year in 78% of cases (10 of 12 evaluable patients) with stabilization of vital capacity. Retrospective data (unpublished) on patients treated in France have shown more side effects and more frequent treatment interruptions and eventually weaker haematological response rate. This study aim to evaluate the benefit of danazol at 12 months on the clinical response.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 40
• Est. completion date: October 20, 2022
• Est. primary completion date: October 20, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 15 Years and older

Eligibility

Inclusion Criteria:

• with telomeropathy defined by the existence of a deleterious constitutional mutation of a gene involved in telomere maintenance (TERT, TERC, DKC1, TINF2, RTEL1, PARN, ACD, NHP2, NOP10, NAF1, WRAP53, CTC1, ERCC6L2, USB1, POT1, DNAJC21 or a newly identified gene responsible for telomeropathy ),

• 15 years or older,

• with severe haematological involvement (platelets < 20 G/L or ANC < 0.5 G/L and/or hemoglobin < 8 g/dL and/or transfusion needs) and/or pulmonary fibrosis with parenchymal involvement greater than 10% on the CT scan.

• being able to give informed consent for patients 18 years and older,

• being able to give consent and have the consent of the holder (s) of parental authority for children over 15 years,

• being a beneficiary of social security scheme.

Exclusion Criteria:

• with HIV infection or active hepatitis B or C infection,

• with severe hepatic disease: ASAT and/or ALAT > 5N, or direct bilirubinemia > 30 µmol/L, TP <50% (except vitamin K deficiency),

• having an active or treated tumor pathology for less than 5 years with the exception of a basocellular carcinoma or a in situ carcinoma of the cervix,

• with a history of organ or hematopoietic stem cell transplantation or with an indication of hematopoietic stem cell or organ transplantation within 6 months of inclusion,

• with an absolute contraindication to treatment with danazol: active thrombosis or history of thromboembolic disease, porphyria, severe renal or cardiac insufficiency (NYHA stage III or IV), androgen-dependent tumor, uncharacterized mammary nodules, pathological genital hemorrhage of undetermined etiology,

• who have already received danazol for the treatment of telomeropathy,

• having received another androgen within a period of less than 6 months,

• receiving another experimental treatment,

• receiving another hormonal therapy,

• receiving simvastatin,

• having a pregnancy plan and not committing to effective contraception while taking the treatment,

• breastfeeding,

• under guardianship or curators.

Related Conditions & MeSH terms

• Telomere Length, Mean Leukocyte
• Telomere Shortening

Intervention

Drug:
• Danazol 200 MG
DANAZOL 200 mg as capsules 800 mg/d orally, in 2 doses Duration of treatment: 12 months

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Assistance Publique - Hôpitaux de Paris

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Hematological response or Pulmonary response at M12	Response at 12 months is defined according to the initial pathology. Responses is defined as a composite outcome. At least one of the following item should be validated to observe response.; For patients with bone marrow failure, the hematological response at 12 months depending on initial cytopenia(s) is defined by; 1.5 g/dL increase in hemoglobin without transfusion for 2 months; And/or increase of 20.10^9/L in platelet count without transfusion for 2 months; And/or increase of 0.5.10^9/L in neutrophils count.; For patients with pulmonary fibrosis, a decrease of less than 5% in forced vital capacity at 12 months	12 months
Secondary	Hepatic tolerance M1	aspartate aminotransferase blood level	1 month
Secondary	Hepatic tolerance M2	aspartate aminotransferase blood level	2 months
Secondary	Hepatic tolerance M3	aspartate aminotransferase blood level	3 months
Secondary	Hepatic tolerance M6	aspartate aminotransferase blood level	6 months
Secondary	Hepatic tolerance M9	aspartate aminotransferase blood level	9 months
Secondary	Hepatic tolerance M12	aspartate aminotransferase blood level	12 months
Secondary	LDL cholesterol M3	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	3 months
Secondary	LDL cholesterol M6	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	6 months
Secondary	LDL cholesterol M9	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	9 months
Secondary	LDL cholesterol M12	Low-density lipoprotein (LDL) cholesterol blood level in mmol/l	12 months
Secondary	HDL cholesterol M3	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	3 months
Secondary	HDL cholesterol M6	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	6 months
Secondary	HDL cholesterol M9	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	9 months
Secondary	HDL cholesterol M12	High-density lipoprotein (LDL) cholesterol blood level in mmol/l	12 months
Secondary	TG M3	triglycerides blood level in mmol/l	3 months
Secondary	TG M6	triglycerides blood level in mmol/l	6 months
Secondary	TG M9	triglycerides blood level in mmol/l	9 months
Secondary	TG M12	triglycerides blood level in mmol/l	12 months
Secondary	PSA M3	Prostate-specific antigen (PSA) blood level for men	3 months
Secondary	PSA M6	Prostate-specific antigen (PSA) blood level for men	6 months
Secondary	PSA M12	Prostate-specific antigen (PSA) blood level for men	12 months
Secondary	Pulmonary parenchymal abnormalities M6	Evolution of pulmonary parenchymal abnormalities at CT scan	6 months
Secondary	Pulmonary parenchymal abnormalities M12	Evolution of pulmonary parenchymal abnormalities at CT scan	12 months
Secondary	Telomere length	Evolution of the telomere length by Flow Fish	12 months
Secondary	cytological and cytogenetic abnormalities	Appearance of cytological and cytogenetic abnormalities (bone marrow aspiration with cytogenetic)	12 months
Secondary	Quality of life evaluation M3	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life).; http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	3 months
Secondary	Quality of life evaluation M6	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life).; http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	6 months
Secondary	Quality of life evaluation M12	European Organisation for Research and Treatment of Cancer Quality of Life of Cancer Patients questionnaire (EORTC QLQ-C30, v3.0). The scale range from to 30 to 126 (30 represents the worse quality of life and 126 the best quality of life).; http://www.eortc.be/qol/files/C30/QLQ-C30%20English.pdf	12 months
Secondary	Overall survival		12 months
Secondary	DLCO M3	Diffusing capacity of the lung for carbon monoxide (DLCO)	3 months
Secondary	DLCO M6	Diffusing capacity of the lung for carbon monoxide (DLCO)	6 months
Secondary	DLCO M9	Diffusing capacity of the lung for carbon monoxide (DLCO)	9 months
Secondary	DLCO M12	Diffusing capacity of the lung for carbon monoxide (DLCO)	12 months