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

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ClinicalTrials.gov Identifier: NCT03710356
Recruitment Status : Not yet recruiting
First Posted : October 18, 2018
Last Update Posted : October 18, 2018
Sponsor:
Information provided by (Responsible Party):
Assistance Publique - Hôpitaux de Paris

Tracking Information
First Submitted Date  ICMJE October 10, 2018
First Posted Date  ICMJE October 18, 2018
Last Update Posted Date October 18, 2018
Estimated Study Start Date  ICMJE October 20, 2018
Estimated Primary Completion Date October 20, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 15, 2018)
Hematological response or Pulmonary response at M12 [ Time Frame: 12 months ]
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
Original Primary Outcome Measures  ICMJE Same as current
Change History No Changes Posted
Current Secondary Outcome Measures  ICMJE
 (submitted: October 15, 2018)
  • Hepatic tolerance M1 [ Time Frame: 1 month ]
    aspartate aminotransferase blood level
  • Hepatic tolerance M2 [ Time Frame: 2 months ]
    aspartate aminotransferase blood level
  • Hepatic tolerance M3 [ Time Frame: 3 months ]
    aspartate aminotransferase blood level
  • Hepatic tolerance M6 [ Time Frame: 6 months ]
    aspartate aminotransferase blood level
  • Hepatic tolerance M9 [ Time Frame: 9 months ]
    aspartate aminotransferase blood level
  • Hepatic tolerance M12 [ Time Frame: 12 months ]
    aspartate aminotransferase blood level
  • LDL cholesterol M3 [ Time Frame: 3 months ]
    Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • LDL cholesterol M6 [ Time Frame: 6 months ]
    Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • LDL cholesterol M9 [ Time Frame: 9 months ]
    Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • LDL cholesterol M12 [ Time Frame: 12 months ]
    Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • HDL cholesterol M3 [ Time Frame: 3 months ]
    High-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • HDL cholesterol M6 [ Time Frame: 6 months ]
    High-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • HDL cholesterol M9 [ Time Frame: 9 months ]
    High-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • HDL cholesterol M12 [ Time Frame: 12 months ]
    High-density lipoprotein (LDL) cholesterol blood level in mmol/l
  • TG M3 [ Time Frame: 3 months ]
    triglycerides blood level in mmol/l
  • TG M6 [ Time Frame: 6 months ]
    triglycerides blood level in mmol/l
  • TG M9 [ Time Frame: 9 months ]
    triglycerides blood level in mmol/l
  • TG M12 [ Time Frame: 12 months ]
    triglycerides blood level in mmol/l
  • PSA M3 [ Time Frame: 3 months ]
    Prostate-specific antigen (PSA) blood level for men
  • PSA M6 [ Time Frame: 6 months ]
    Prostate-specific antigen (PSA) blood level for men
  • PSA M12 [ Time Frame: 12 months ]
    Prostate-specific antigen (PSA) blood level for men
  • Pulmonary parenchymal abnormalities M6 [ Time Frame: 6 months ]
    Evolution of pulmonary parenchymal abnormalities at CT scan
  • Pulmonary parenchymal abnormalities M12 [ Time Frame: 12 months ]
    Evolution of pulmonary parenchymal abnormalities at CT scan
  • Telomere length [ Time Frame: 12 months ]
    Evolution of the telomere length by Flow Fish
  • cytological and cytogenetic abnormalities [ Time Frame: 12 months ]
    Appearance of cytological and cytogenetic abnormalities (bone marrow aspiration with cytogenetic)
  • Quality of life evaluation M3 [ Time Frame: 3 months ]
    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
  • Quality of life evaluation M6 [ Time Frame: 6 months ]
    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
  • Quality of life evaluation M12 [ Time Frame: 12 months ]
    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
  • Overall survival [ Time Frame: 12 months ]
  • DLCO M3 [ Time Frame: 3 months ]
    Diffusing capacity of the lung for carbon monoxide (DLCO)
  • DLCO M6 [ Time Frame: 6 months ]
    Diffusing capacity of the lung for carbon monoxide (DLCO)
  • DLCO M9 [ Time Frame: 9 months ]
    Diffusing capacity of the lung for carbon monoxide (DLCO)
  • DLCO M12 [ Time Frame: 12 months ]
    Diffusing capacity of the lung for carbon monoxide (DLCO)
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Evaluating Efficacy and Safety of Danazol in Severe Hematologic or Pulmonary Disease Related to Telomeropathy
Official Title  ICMJE 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
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.

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description:
phase ½ therapeutic trial stratified on disease (Severe Hematologic or Pulmonary Disease)
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Telomere Shortening
  • Telomere Length, Mean Leukocyte
Intervention  ICMJE Drug: Danazol 200 MG
DANAZOL 200 mg as capsules 800 mg/d orally, in 2 doses Duration of treatment: 12 months
Study Arms  ICMJE Experimental: Danazol
Danazol
Intervention: Drug: Danazol 200 MG
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: October 15, 2018)
40
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE October 20, 2022
Estimated Primary Completion Date October 20, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 15 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Flore SICRE DE FONTBRUNE, MD PhD 142494949 ext +33 flore.sicre-de-fontbrune@aphp.fr
Contact: Matthieu RESCHE-RIGON, MD PhD 142499742 ext +33 matthieu.resche-rigon@univ-paris-diderot.fr
Listed Location Countries  ICMJE Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03710356
Other Study ID Numbers  ICMJE P170925J
2018-001686-17 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Assistance Publique - Hôpitaux de Paris
Study Sponsor  ICMJE Assistance Publique - Hôpitaux de Paris
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Assistance Publique - Hôpitaux de Paris
Verification Date October 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP