Telomere ShorteningPhase 1/2ANDROTELONCT03710356
Evaluating Efficacy and Safety of Danazol in Severe Hematologic or Pulmonary Disease Related to Telomeropathy
A Phase 1/2 study testing Danazol 200 MG in people with Telomere Shortening and Telomere Length, Mean Leukocyte, run by Assistance Publique - Hôpitaux de Paris.
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. Read more about this study
- Who is it for?
- Ages 15 years and older
- Conditions the study is for
- Telomere Shortening, Telomere Length, Mean Leukocyte
- What is being tested?
- Danazol 200 MG
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 40 participants
- Where
- No sites listed yet
- Study dates
- 20 Oct 2018to 20 Oct 2022
- Phase
- Phase 1/2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 years and older
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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,
Show all 13Show fewer
- 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.
Trial locations and contacts
No sites are listed yet.
About this study
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
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.
- Being tested
- Danazol 200 MG
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Danazol 200 MGDrug
DANAZOL 200 mg as capsules 800 mg/d orally, in 2 doses Duration of treatment: 12 months
| Study group | Role | What they receive |
|---|---|---|
| Danazol | Experimental | Danazol Receives: Drug: Danazol 200 MG |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: 12 months
Secondary outcomes (33)
Hepatic tolerance M1
aspartate aminotransferase blood level
Measured: 1 month
Hepatic tolerance M2
aspartate aminotransferase blood level
Measured: 2 months
Hepatic tolerance M3
aspartate aminotransferase blood level
Measured: 3 months
Hepatic tolerance M6
aspartate aminotransferase blood level
Measured: 6 months
Hepatic tolerance M9
aspartate aminotransferase blood level
Measured: 9 months
Hepatic tolerance M12
aspartate aminotransferase blood level
Measured: 12 months
LDL cholesterol M3
Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 3 months
LDL cholesterol M6
Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 6 months
LDL cholesterol M9
Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 9 months
LDL cholesterol M12
Low-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 12 months
HDL cholesterol M3
High-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 3 months
HDL cholesterol M6
High-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 6 months
HDL cholesterol M9
High-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 9 months
HDL cholesterol M12
High-density lipoprotein (LDL) cholesterol blood level in mmol/l
Measured: 12 months
TG M3
triglycerides blood level in mmol/l
Measured: 3 months
TG M6
triglycerides blood level in mmol/l
Measured: 6 months
TG M9
triglycerides blood level in mmol/l
Measured: 9 months
TG M12
triglycerides blood level in mmol/l
Measured: 12 months
PSA M3
Prostate-specific antigen (PSA) blood level for men
Measured: 3 months
PSA M6
Prostate-specific antigen (PSA) blood level for men
Measured: 6 months
PSA M12
Prostate-specific antigen (PSA) blood level for men
Measured: 12 months
Pulmonary parenchymal abnormalities M6
Evolution of pulmonary parenchymal abnormalities at CT scan
Measured: 6 months
Pulmonary parenchymal abnormalities M12
Evolution of pulmonary parenchymal abnormalities at CT scan
Measured: 12 months
Telomere length
Evolution of the telomere length by Flow Fish
Measured: 12 months
cytological and cytogenetic abnormalities
Appearance of cytological and cytogenetic abnormalities (bone marrow aspiration with cytogenetic)
Measured: 12 months
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
Measured: 3 months
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
Measured: 6 months
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
Measured: 12 months
Overall survival
Measured: 12 months
DLCO M3
Diffusing capacity of the lung for carbon monoxide (DLCO)
Measured: 3 months
DLCO M6
Diffusing capacity of the lung for carbon monoxide (DLCO)
Measured: 6 months
DLCO M9
Diffusing capacity of the lung for carbon monoxide (DLCO)
Measured: 9 months
DLCO M12
Diffusing capacity of the lung for carbon monoxide (DLCO)
Measured: 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Oct 2018
- Study start20 Oct 2018 (estimated)
- Primary completion20 Oct 2021 (estimated)
- Study completion20 Oct 2022 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Telomere ShorteningStudies of the same condition, open and under way.
- More trials run by Assistance Publique - Hôpitaux de ParisThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- phase ½ therapeutic trial stratified on disease (Severe Hematologic or Pulmonary Disease)
- Masking
- None (open label)
- Enrolment
- 40 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assistance Publique - Hôpitaux de Paris
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03710356
- Sponsor's protocol ID
- P170925J
- Other IDs
- 2018-001686-17, 2018
- Acronym
- ANDROTELO
- Status last verified
- Oct 2018
- First submitted
- 10 Oct 2018
- Last updated
- 18 Oct 2018
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 18 Oct 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT03710356
- Acronym / sponsor ID
- ANDROTELO / P170925J
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 40 participants (estimated)
- Lead sponsor
- Assistance Publique - Hôpitaux de ParisUniversity, hospital or other
- Study start
- 20 Oct 2018 (estimated)
- Primary completion
- 20 Oct 2021 (estimated)
- Study completion
- 20 Oct 2022 (estimated)
- First posted
- 18 Oct 2018 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- phase ½ therapeutic trial stratified on disease (Severe Hematologic or Pulmonary Disease)
| Arm | Type | Receives |
|---|---|---|
| Danazol | Experimental | Drug: Danazol 200 MGDanazol |
Who may qualify
- Ages
- 15 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- 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,
Key exclusion criteria (13 listed)
- 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,
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Danazol 200 MGDANAZOL 200 mg as capsules 800 mg/d orally, in 2 doses Duration of treatment: 12 months | Drug | Danazol |
Primary outcome
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
33 secondary outcomes
Hepatic tolerance M1
Time frame: 1 month
Hepatic tolerance M2
Time frame: 2 months
Hepatic tolerance M3
Time frame: 3 months
Hepatic tolerance M6
Time frame: 6 months
Hepatic tolerance M9
Time frame: 9 months
Hepatic tolerance M12
Time frame: 12 months
LDL cholesterol M3
Time frame: 3 months
LDL cholesterol M6
Time frame: 6 months
LDL cholesterol M9
Time frame: 9 months
LDL cholesterol M12
Time frame: 12 months
HDL cholesterol M3
Time frame: 3 months
HDL cholesterol M6
Time frame: 6 months
HDL cholesterol M9
Time frame: 9 months
HDL cholesterol M12
Time frame: 12 months
TG M3
Time frame: 3 months
TG M6
Time frame: 6 months
TG M9
Time frame: 9 months
TG M12
Time frame: 12 months
PSA M3
Time frame: 3 months
PSA M6
Time frame: 6 months
PSA M12
Time frame: 12 months
Pulmonary parenchymal abnormalities M6
Time frame: 6 months
Pulmonary parenchymal abnormalities M12
Time frame: 12 months
Telomere length
Time frame: 12 months
cytological and cytogenetic abnormalities
Time frame: 12 months
Quality of life evaluation M3
Time frame: 3 months
Quality of life evaluation M6
Time frame: 6 months
Quality of life evaluation M12
Time frame: 12 months
Overall survival
Time frame: 12 months
DLCO M3
Time frame: 3 months
DLCO M6
Time frame: 6 months
DLCO M9
Time frame: 9 months
DLCO M12
Time frame: 12 months
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 18 Oct 2018.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing Danazol 200 MG in people with Telomere Shortening and Telomere Length, Mean Leukocyte, run by Assistance Publique - Hôpitaux de Paris.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 18 Oct 2018. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Flore SICRE DE FONTBRUNE, MD PhD (142494949 ext. +33, flore.sicre-de-fontbrune@aphp.fr), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Hematological response or Pulmonary response at M12 (time frame: 12 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Oct 2018.