Clinical trial NCT02559648: Denosumab vs Placebo in Patients With Thalassemia Major and Osteoporosis
Official title: Evaluation of Efficacy of Denosumab in Patients With Thalassemia Major and Osteoporosis: A Randomized, Placebo-controlled, Single-site, Double Blind Phase 2b Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Thalassemia Major
Osteoporosis
Lead sponsor: Laikο General Hospital, Athens
Sponsor class: OTHER
First posted: 2015-09-24
Enrollment: 63
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is a single-site, randomized, placebo-controlled, double blind phase 2b clinical trial. Patients with Thalassemia will participate in this study and will be treated with Denosumab or placebo. The effect of Denosumab on lumbar spine BMD in patients with Thalassemia Major and Osteoporosis will be evaluated as compared with control (placebo) at 12 months.

Detailed description: This is a single-site, randomized, placebo-controlled, double blind phase 2b clinical trial. Patients with Thalassemia and Bone Mass Density (BMD) T-score between -2.5 and - 4.0 in at least one of the examined sites will participate in this study and will be treated with Denosumab or placebo.

Patients will be assigned into two (2) treatment groups:

* In Group A, 60 mg Denosumab will be administered sc, every 6 months for 12 months for a total of 2 doses (day 0 and day 180).
* In Group B placebo will be administered sc, every 6 months for 12 months for a total of 2 doses (day 0 and day 180) (Appendix I and Appendix II).

Patients will be randomly assigned, in a 1:1 fashion, to the two therapeutic arms (Group A, Group B, respectively), upon enrollment in the study.

The effect of Denosumab on lumbar spine BMD (bone mineral density) in patients with Thalassemia Major and Osteoporosis as compared with control at 12 months will be evaluated. Also the effect on femoral neck and wrist bone BMD, on markers of bone remodeling and the safety profile will be evaluated as well. All subjects will receive a subcutaneous injection of Denosumab or placebo administered by a health care professional on days 0 and 180 (±3).

Eligibility criteria: Inclusion Criteria:

* Adults (\>30 years of age) described as skeletally mature subjects
* Thalassemia Major
* Low BMD (T-score \<-2.5) in one of the 3 studied sites (lumbar spine, femoral neck, wrist).
* Have signed the informed consent form (consent should be taken before any study-specific procedure is performed).

Exclusion Criteria:

* BMD T-score \< -4.0 in one of the 2 studied sites (lumbar spine, femoral neck).
* Previous administration of denosumab from clinical trials or others (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 (using the Chronic Kidney Disease-Epidemiology, ((CKD-EPI) formula).
* Patients with sickle cell disease.
* Known to have a liver failure or chronic hepatic disease e.g. cirrhosis, chronic hepatitis; or elevated transaminases defined as Alanine Transaminase (ALT) and/or Aspartate Transaminase (AST) \> 2 fold the upper limit of normal laboratory range.
* Heart failure (NYHA above 2).
* Patients with life expectancy of less than one year.
* Subject refuses to use a reliable contraceptive method (oral contraceptives, progesterone implants, intrauterine device, condoms) throughout the study by women of childbearing potential. Women of childbearing potential agree to use 2 highly effective forms of contraception and to continue this practice for 7 months after last injection of study medication.
* 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 or any other condition associated with poor compliance
* 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.
* Parathormone (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 or calcitriol use within the last 6 weeks.
* Evidence of hyper- or hypothyroidism; patients with an abnormal Thyroid stimulating hormone (TSH) level on thyroid treatment (patients on stable thyroid treatment with a normal TSH allowed); current hyper- or hypoparathyroidism; current hyper or hypocalcemia (hypocalcemia based on albumin adjusted serum calcium \< 8.5 mg/dL); vitamin D deficiency (25-hydroxy Vitamin D level \< 12 ng/mL; if repeat 12-20 ng/mL after repletion, subject will be allowed); rheumatoid arthritis; Paget's disease; bone disease that would interfere with interpretation of findings.
* Known sensitivity to mammalian cell-derived drug products.
* 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.

Primary outcomes:
measure: The percent change in the lumbar spine BMD
timeFrame: 12 months
Secondary outcomes:
measure: The percent change in BMD of the total hip and femoral neck
timeFrame: 12 months
measure: The percent change in BMD at the distal third radius
timeFrame: 12 months
measure: The percent change in serum C-Termina Telopeptide (sCTX) at Month 3 post injection
timeFrame: 3 months
Other outcomes:
measure: Adverse event incidence by system organ class and preferred term
timeFrame: 12 months
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 12 months
measure: Changes in general appearance at each visit
timeFrame: 12 months
measure: Changes in skin contour at each visit
timeFrame: 12 months
measure: Changes in cardiology clinical examination at each visit
timeFrame: 12 months
measure: Changes in ECG at each visit
timeFrame: 12 months
Locations:
city: Athens
country: Greece
facility: General Hospital of Athens "Laikon"
state: Attica
Study officials:
affiliation: General Hospital of Athens "Laikon"
name: Ersi Voskaridou, Doctor
role: PRINCIPAL_INVESTIGATOR
References:
citation: Voskaridou E, Ntanasis-Stathopoulos I, Papaefstathiou A, Christoulas D, Dimopoulou M, Repa K, Papatheodorou A, Peppa M, Terpos E. Denosumab in transfusion-dependent thalassemia osteoporosis: a randomized, placebo-controlled, double-blind phase 2b clinical trial. Blood Adv. 2018 Nov 13;2(21):2837-2847. doi: 10.1182/bloodadvances.2018023085.