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

NCT03710356 | Unknown Phase 1 DMC

• 2 other identifiers: P170925J2018-001686-17
• Study Type: interventional
• Target: 40
• Locations: 0 countries
• Sites: N/A

Brief 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 Retrospective data (unpublished) on patients treated in France have shown more side effects and more frequent treatment interruptions and eventually weaker haematological response rate.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.

Conditions

Telomere Shortening; Telomere Length, Mean Leukocyte

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (33)

• Hepatic tolerance M1

  1 month

• Hepatic tolerance M2

  2 months

• Hepatic tolerance M3

  3 months

• Hepatic tolerance M6

  6 months

• Hepatic tolerance M9

  9 months

Study Arms (1)

Danazol

EXPERIMENTAL

Danazol

Drug: Danazol 200 MG

Interventions

Danazol 200 MG DRUG

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

Danazol

Eligibility Criteria

• Age: 15 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ),
• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

MeSH Terms

Interventions

Danazol

Intervention Hierarchy (Ancestors)

Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Central Study Contacts

Flore SICRE DE FONTBRUNE, MD PhD

CONTACT

142494949; flore.sicre-de-fontbrune@aphp.fr

Matthieu RESCHE-RIGON, MD PhD

CONTACT

142499742; matthieu.resche-rigon@univ-paris-diderot.fr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: phase ½ therapeutic trial stratified on disease (Severe Hematologic or Pulmonary Disease)

Study Record Dates

• First Submitted: October 10, 2018
• First Posted: October 18, 2018
• Study Start: October 20, 2018
• Primary Completion: October 20, 2021
• Study Completion: October 20, 2022
• Last Updated: October 18, 2018

Record last verified: 2018-10

Data Sharing

• IPD Sharing: Will not share