Langerhans Cell HistiocytosisPhase 2NCT03270020
Denosumab for the Treatment of Adult LCH
A Phase 2 study testing Denosumab 70 MG/ML [Xgeva] in people with Langerhans Cell Histiocytosis, run by Hellenic Society for the Study of Bone Metabolism at 1 site in Greece.
Trial summary
This study is aiming to evaluate the efficacy of denosumab among adult patients suffering from Langerhans Cell Histiocytosis (LCH). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Langerhans Cell Histiocytosis
- What is being tested?
- Denosumab 70 MG/ML [Xgeva]
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 10 participants
- Where
- 1 siteGreece
- Study dates
- 7 Sep 2017to 14 Jan 2025
- Phase
- Phase 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 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Adults (>18 years of age)
- Definitive diagnosis of LCH [Based on clinic-pathological evidence with microscopic examination and at least one of the following immunological staining: Langerin (CD 207) positivity, Cluster of Differentiation 1a (CD1a) positivity, Presence of Birbeck granules on electronic microscopy]
- Mild symptoms (symptoms of low intensity; no need for hospitalization) and low risk disease needing first line systemic therapy for LCH because of:
- single system disease with multifocal lesions, or
- single system disease with "special site" lesions (vertebral lesions with intraspinal extension, craniofacial bone lesions with soft tissue extension), or
- multi-system disease without involvement of risk organs [hematopoietic system, spleen, liver, tumorous central nervous system (CNS)].
- Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).
- A patient should undergo a PET-CT imaging test, in order for him to be deemed suitable for the study. The initial PET-CT either may have been carried out, within 3 months prior to visit 1, regardless of the diagnostic center or the type of the device, which has been used for, or may take place in the context of visit 2, at the diagnostic center(s) specialized on Nuclear Medicine, which have been partnered with the Sponsor. Whichever is the case, the initial PET-CT report should be legible and accurate, so that to be assessed by the qualified physician, responsible for the PET-CT test at the partnered diagnostic center(s).
Who cannot join
- Symptomatic multi system LCH - no risk organs involved.
- Multi-system LCH (with or without symptoms) - risk organs involved.
- Isolated pulmonary LCH disease
- Previous administration of denosumab from clinical trials or other use (e.g. commercial use).
- Current participation in another clinical trial or having received any investigational product within the last 3 months.
- Impaired renal function as determined by an estimated glomerular filtration rate (eGFR) of ≤ 30 mL/min/1,73m2 [using the Chronic Kidney Disease-Epidemiology, (CKD-EPI) formula].
Show all 23Show fewer
- Patients that have received oral bisphosphonates within 6 months of study enrollment or intravenous bisphosphonates, fluoride and strontium ranelate within 1 year of study enrollment.
- Treatment with immune suppressive agents within 4 weeks from baseline evaluation.
- Patients with severe impairment of clinical condition including: severely impaired pulmonary function [for example total lung capacity (TLC)<60%, forced expiratory volume 1 (FEV1)<30%, diffusing capacity of the lungs for carbon monoxide (DLCO)<30%, partial pressure of oxygen (PaO2)<55 mmHg), long term oxygen therapy or cor pulmonale.
- Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic hepatitis; or elevated transaminases defined as alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 2 fold the upper limit of normal laboratory range.
- Heart failure [New York Heart Association (NYHA) Functional Classification above 2].
- Patients with life expectancy of less than one year.
- Female subjects of childbearing potential who refuse to use a reliable contraceptive method throughout the study, defined as use of 2 highly effective forms of contraception and continuation of use for 7 months after last administration of study drug. Birth control methods that can achieve a failure rate of less than 1% per year, when used consistently and correctly, are considered as highly effective.
- Pregnancy, planning a pregnancy or currently lactating
- Severe concurrent illness which in the investigator's opinion may confound patient evaluation, e.g. malignancy (except basal cell carcinoma, cervical or breast ductal carcinoma in situ) within the last 5 years.
- Known alcohol or drug abuse.
- Parathyroid hormone (PTH), PTH derivatives, teriparatide, odanacatib, anabolic steroids, testosterone, glucocorticosteroids (> 5 mg/day of prednisone equivalent for > 10 days), systemic hormone-replacement therapy, selective estrogen receptor modulators (SERMs), raloxifene, tibolone, calcitonin use within the last 6 weeks.
- Evidence of hyper- or hypothyroidism; patients with an abnormal thyroid stimulate hormone (TSH) level on thyroid treatment (patients on stable thyroid treatment with a normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or hypocalcemia (hypercalcemia based on albumin adjusted serum calcium > 10.40 mg/dL; hypocalcemia based on albumin adjusted serum calcium < 8.5 mg/dL); vitamin D deficiency (25-hydroxy vitamin D level < 20 ng/mL; if the resulted value of the retest is 20 ≥ ng/Ml, after repletion with 50,000 - 100,000 IU of cholecalciferol, subject will be allowed. The retest should be carried out within 30 days post to visit 1(screening)); rheumatoid arthritis; Paget's disease; any known bone disease with osteolytic and/or osteoblastic lesions that would interfere with interpretation of findings.
- Known sensitivity to mammalian cells, denosumab or any components of denosumab 120mg, or any of the products to be administered during the study (e.g., calcium or vitamin D).
- History of any Solid Organ or Bone Marrow Transplant.
- History of osteonecrosis of the jaw, and/or recent tooth extraction or other dental surgery; or planned invasive dental work during the study.
- Intolerance to calcium supplements.
- Malabsorption syndrome; severe malabsorption including Celiac disease, Short Bowel Syndrome, Crohn's disease, Previous Gastric Bypass.
Trial locations and contacts
1 site in 1 country.
Greece1 site
251 Hellenic AirForce & VA General Hospital, Dpt of Endocrinology
Athens, Attica, 11525
About this study
Official title: Evaluation of Efficacy of Denosumab in Adult Patients With Langerhans Cell Histiocytosis (LCH): a Multiple-site, Single Arm, Open Label Clinical Trial
This study is aiming to evaluate the efficacy of denosumab among adult patients suffering from Langerhans Cell Histiocytosis (LCH).
Read the detailed description
The majority and diversity of clinical manifestations in LCH are attributed to immunological dysfunction resulting from langerhans cell (LC) derived cytokine secretion both at the lesional and systemic level. In a recent study, Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) was found to be abundantly expressed in cells within diverse LCH lesions from adult patients, especially in inflammatory infiltrates, a finding in line with a previously reported high osteoprotegerin (OPG) and low RANKL levels in the serum of patients with or without bone involvement. RANKL expression was associated with concomitant p65 Nuclear Factor Kappa-B (NFκB) nuclear staining, the main downstream effector of RANKL signaling, suggesting that lesional cell activation may be triggered locally by RANKL. Combining the serum and the lesional results, it can be inferred that there is an ongoing process of countervailing OPG production against lesional RANKL, which could be one of the self defense mechanisms among LCH patients. Therefore, the use of denosumab seems a rational treatment option in LCH in order to support and enhance the defensive OPG action and hopefully control or even interrupt the lesional immunological process.
The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg every 8 weeks (Q8W) sc in adult LCH patients.
Secondary Objectives:
- To define an uniform treatment approach for LCH patients with mild symptoms and low risk disease.
- To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations after treatment completion.
- To illustrate the safety profile of denosumab in LCH patients. The primary efficacy endpoint is defined as the percentage of patients with progression of disease at Month 8.
- Conditions
- Langerhans Cell Histiocytosis
- Being tested
- Denosumab 70 MG/ML [Xgeva]
- Keywords
- treatment, denosumab, Positron Emission Tomography (PET) CT scan
- Medical subject headings
- Histiocytosis, Langerhans-Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Denosumab 70 MG/ML [Xgeva]Drug
Also called Xgeva
As already described in arm description
| Study group | Role | What they receive |
|---|---|---|
| Treatment arm | Experimental | This is a single arm study; the study arm include all patients participating in the study who will all receive Denosumab 70 MG/ML [Xgeva] Receives: Drug: Denosumab 70 MG/ML [Xgeva] |
What is being measured
The primary outcome is the main question the study is designed to answer.
Primary efficacy endpoint: effect of denosumab treatment on the activity status of the disease (Incidence of patients with active disease)
The primary efficacy endpoint will be measured through the incidence of patients with active disease at Month 8. Given that all patients have active disease at baseline the incidence of patients with active disease at Month 8 will provide the efficacy of denosumab in controlling the disease within this time frame.
Measured: 8 months
Secondary outcomes (1)
Secondary efficacy endpoint: development of disease-related permanent sequelae during the study period (Incidence of disease-related permanent sequelae)
Incidence of disease-related permanent sequelae, developed during the study, at month 18. In specific, permanent sequelae such as diabetes insipidus, anterior pituitary deficiencies, and pulmonary failure will be assessed at the end of the study in order to evaluate the efficacy of denosumab in preventing those conditions.
Measured: 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Sep 2017
- Study start7 Sep 2017
- Primary completion22 Jun 2022
- Study completion14 Jan 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for Langerhans Cell HistiocytosisStudies of the same condition, open and under way.
- 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 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- The investigational arm will recruit patients who will receive denosumab 120mg sc every 2 months. The estimated duration of the recruitment period is 12 months. The treatment period would be 6 months (denosumab administration on months: 0, 2, 4, 6) and the follow-up period would be 12 months.
- Masking
- None (open label)
- Enrolment
- 10 participants (actual)
Sponsor and investigators
- Lead sponsor
- Hellenic Society for the Study of Bone Metabolism
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Polyzois Makras, MD, PhD, Principal investigator, Dpt of Endocrinology & Diabetes, 251 Hellenic AirForce & VA General Hospital, Athens, Greece
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03270020
- Sponsor's protocol ID
- 20159460
- Status last verified
- Jan 2025
- First submitted
- 26 Aug 2017
- Last updated
- 15 Jan 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Makras P, Tsoli M, Anastasilakis AD, Thanou M, Kaltsas G. Denosumab for the treatment of adult multisystem Langerhans cell histiocytosis. Metabolism. 2017 Apr;69:107-111. doi: 10.1016/j.metabol.2017.01.004. Epub 2017 Jan 12.
PubMed 28285639Makras P, Salagianni M, Revelos K, Anastasilakis AD, Schini M, Tsoli M, Kaltsas G, Andreakos E. Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2015 Feb;100(2):E282-6. doi: 10.1210/jc.2014-2654. Epub 2014 Nov 6.
PubMed 25375981Makras P, Polyzos SA, Anastasilakis AD, Terpos E, Kanakis G, Schini M, Papatheodorou A, Kaltsas GA. Serum osteoprotegerin, RANKL, and Dkk-1 levels in adults with Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2012 Apr;97(4):E618-21. doi: 10.1210/jc.2011-2962. Epub 2012 Jan 25.
PubMed 22278426Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, de Menthon M, Micke O, Passoni E, Seegenschmiedt HM, Tazi A, McClain KL. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013 May 14;8:72. doi: 10.1186/1750-1172-8-72.
PubMed 23672541
Study at a glance
From the registry record, last updated by the sponsor on 15 Jan 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Evaluation of Efficacy of Denosumab in Adult Patients With Langerhans Cell Histiocytosis (LCH): a Multiple-site, Single Arm, Open Label Clinical Trial
- ClinicalTrials.gov ID
- NCT03270020
- Acronym / sponsor ID
- 20159460
- Conditions
- Langerhans Cell Histiocytosis
- Keywords
- treatment, denosumab, Positron Emission Tomography (PET) CT scan
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 10 participants (actual)
- Lead sponsor
- Hellenic Society for the Study of Bone MetabolismUniversity, hospital or other
- Study start
- 7 Sep 2017 (actual)
- Primary completion
- 22 Jun 2022 (actual)
- Study completion
- 14 Jan 2025 (actual)
- First posted
- 1 Sep 2017 (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.
This study is aiming to evaluate the efficacy of denosumab among adult patients suffering from Langerhans Cell Histiocytosis (LCH).
Detailed description
The majority and diversity of clinical manifestations in LCH are attributed to immunological dysfunction resulting from langerhans cell (LC) derived cytokine secretion both at the lesional and systemic level. In a recent study, Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL) was found to be abundantly expressed in cells within diverse LCH lesions from adult patients, especially in inflammatory infiltrates, a finding in line with a previously reported high osteoprotegerin (OPG) and low RANKL levels in the serum of patients with or without bone involvement. RANKL expression was associated with concomitant p65 Nuclear Factor Kappa-B (NFκB) nuclear staining, the main downstream effector of RANKL signaling, suggesting that lesional cell activation may be triggered locally by RANKL. Combining the serum and the lesional results, it can be inferred that there is an ongoing process of countervailing OPG production against lesional RANKL, which could be one of the self defense mechanisms among LCH patients. Therefore, the use of denosumab seems a rational treatment option in LCH in order to support and enhance the defensive OPG action and hopefully control or even interrupt the lesional immunological process.
The primary study objective is to assess the therapeutic efficacy of denosumab 120 mg every 8 weeks (Q8W) sc in adult LCH patients.
Secondary Objectives:
- To define an uniform treatment approach for LCH patients with mild symptoms and low risk disease.
- To explore the efficacy of denosumab 120 mg Q8W sc in reducing disease reactivations after treatment completion.
- To illustrate the safety profile of denosumab in LCH patients. The primary efficacy endpoint is defined as the percentage of patients with progression of disease at Month 8.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- The investigational arm will recruit patients who will receive denosumab 120mg sc every 2 months. The estimated duration of the recruitment period is 12 months. The treatment period would be 6 months (denosumab administration on months: 0, 2, 4, 6) and the follow-up period would be 12 months.
| Arm | Type | Receives |
|---|---|---|
| Treatment arm | Experimental | Drug: Denosumab 70 MG/ML [Xgeva]This is a single arm study; the study arm include all patients participating in the study who will all receive Denosumab 70 MG/ML [Xgeva] |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (8 listed)
- Adults (>18 years of age)
- Definitive diagnosis of LCH [Based on clinic-pathological evidence with microscopic examination and at least one of the following immunological staining: Langerin (CD 207) positivity, Cluster of Differentiation 1a (CD1a) positivity, Presence of Birbeck granules on electronic microscopy]
- Mild symptoms (symptoms of low intensity; no need for hospitalization) and low risk disease needing first line systemic therapy for LCH because of:
- Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).
- A patient should undergo a PET-CT imaging test, in order for him to be deemed suitable for the study. The initial PET-CT either may have been carried out, within 3 months prior to visit 1, regardless of the diagnostic center or the type of the device, which has been used for, or may take place in the context of visit 2, at the diagnostic center(s) specialized on Nuclear Medicine, which have been partnered with the Sponsor. Whichever is the case, the initial PET-CT report should be legible and accurate, so that to be assessed by the qualified physician, responsible for the PET-CT test at the partnered diagnostic center(s).
Key exclusion criteria (23 listed)
- Symptomatic multi system LCH - no risk organs involved.
- Multi-system LCH (with or without symptoms) - risk organs involved.
- Isolated pulmonary LCH disease
- Previous administration of denosumab from clinical trials or other use (e.g. commercial use).
- Current participation in another clinical trial or having received any investigational product within the last 3 months.
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 |
|---|---|---|
| Denosumab 70 MG/ML [Xgeva]Also: XgevaAs already described in arm description | Drug | Treatment arm |
Primary outcome
Primary efficacy endpoint: effect of denosumab treatment on the activity status of the disease (Incidence of patients with active disease)
Time frame: 8 months
The primary efficacy endpoint will be measured through the incidence of patients with active disease at Month 8. Given that all patients have active disease at baseline the incidence of patients with active disease at Month 8 will provide the efficacy of denosumab in controlling the disease within this time frame.
1 secondary outcome
Secondary efficacy endpoint: development of disease-related permanent sequelae during the study period (Incidence of disease-related permanent sequelae)
Time frame: 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Jan 2025.
- Background: PubMed 28285639Makras P, Tsoli M, Anastasilakis AD, Thanou M, Kaltsas G. Denosumab for the treatment of adult multisystem Langerhans cell histiocytosis. Metabolism. 2017 Apr;69:107-111. doi: 10.1016/j.metabol.2017.01.004. Epub 2017 Jan 12.
- Background: PubMed 25375981Makras P, Salagianni M, Revelos K, Anastasilakis AD, Schini M, Tsoli M, Kaltsas G, Andreakos E. Rationale for the application of RANKL inhibition in the treatment of Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2015 Feb;100(2):E282-6. doi: 10.1210/jc.2014-2654. Epub 2014 Nov 6.
- Background: PubMed 22278426Makras P, Polyzos SA, Anastasilakis AD, Terpos E, Kanakis G, Schini M, Papatheodorou A, Kaltsas GA. Serum osteoprotegerin, RANKL, and Dkk-1 levels in adults with Langerhans cell histiocytosis. J Clin Endocrinol Metab. 2012 Apr;97(4):E618-21. doi: 10.1210/jc.2011-2962. Epub 2012 Jan 25.
- Background: PubMed 23672541Girschikofsky M, Arico M, Castillo D, Chu A, Doberauer C, Fichter J, Haroche J, Kaltsas GA, Makras P, Marzano AV, de Menthon M, Micke O, Passoni E, Seegenschmiedt HM, Tazi A, McClain KL. Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net. Orphanet J Rare Dis. 2013 May 14;8:72. doi: 10.1186/1750-1172-8-72.
- 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.
Polyzois Makras, MD, PhD principal investigator
Dpt of Endocrinology & Diabetes, 251 Hellenic AirForce & VA General Hospital, Athens, Greece
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Denosumab 70 MG/ML [Xgeva] in people with Langerhans Cell Histiocytosis, run by Hellenic Society for the Study of Bone Metabolism at 1 site in Greece.
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 8 inclusion and 23 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: finished, as of the sponsor's last update on 15 Jan 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Greece. Whether a site is taking part right now should be confirmed with that site. See every site.
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 phase mean?
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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Primary efficacy endpoint: effect of denosumab treatment on the activity status of the disease (Incidence of patients with active disease) (time frame: 8 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03270020, which also lists 4 linked publications.
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 15 Jan 2025.