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Trial record 5 of 167 for:    Recruiting, Not yet recruiting, Available Studies | Osteoporosis

Novel Combination Therapy for Osteoporosis in Men (Osteo-Men)

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ClinicalTrials.gov Identifier: NCT03994172
Recruitment Status : Not yet recruiting
First Posted : June 21, 2019
Last Update Posted : July 1, 2019
Sponsor:
Collaborator:
University of California, San Francisco
Information provided by (Responsible Party):
VA Office of Research and Development

Brief Summary:
Osteoporotic fractures are a key health problem in older men. Although there are drugs approved to treat osteoporosis in men [bisphosphonates, denosumab, and teriparatide (TPTD) or PTH(1-34)], there is a lack of knowledge on how to use them effectively. TPTD is a potent bone anabolic drug, meaning that it builds bone mass. However, doctors do not know if it should only be used as single drug or whether it can be more effectively combined to achieve the most benefit? This trial will test a novel combination therapy for osteoporosis in men based on exciting laboratory findings in mice. TPTD works to raise bone mass and improve bone strength by stimulating PTH receptors (PTH-Rs) on the membranes of bone-forming cells or osteoblasts (OBs). Calcimimetics are drugs that activate calcium receptors (CaSRs) in OBs. CaSRs in OBs participate in new bone formation. Daily injections of TPTD, given along with a calcimimetic drug (called NPS-R568), over 6 weeks markedly improved bone mineral density (BMD) and structure in mice. This study will test whether the combined activation of PTH-Rs and CaSRs (by the combination treatment of TPTD+calcimimetic cinacalcet) in men will produce greater bone forming responses than PTH-R activation alone (TPTD+placebo). The study has two aims and will be done in 48 men with low bone mass: (1) to determine the effects of 11 months treatment with TPTD+cinacalcet vs TPTD+placebo on BMD and bone metabolism by assessing lumbar spine BMD (primary endpoint), femoral neck BMD, and levels of the bone formation marker serum N-terminal pro-peptide of type 1 collagen; (2) to determine the biochemical responses by blood tests in men who receive the combination of TPTD+cinacalcet compared to men who get TPTD+placebo treatment. This is done by quantifying acute and chronic changes in serum calcium and PTH levels right after these drugs are given and how much calcium is excreted in the urine over time, with both treatment regimens. This study will help to understand whether an effective combination therapy in mice will prove to be effective in men.

Condition or disease Intervention/treatment Phase
Male Osteoporosis Drug: Teriparatide or human parathyroid hormone (PTH) 1-34 Drug: Cinacalcet Drug: placebo tablet Dietary Supplement: Calcium citrate tablet Dietary Supplement: Vitamin D3 Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: The study design is that of a randomized double-blind, placebo (PBO)-controlled trial of the combination of teriparatide (TPTD) + the calcimimetic cinacalcet compared to monotherapy with TPTD alone in men with low bone mineral density (BMD).
Masking: Triple (Participant, Care Provider, Investigator)
Masking Description: All study personnel will be masked to treatment assignment and this group will include the DXA technicians, the study coordinators, and the lab technicians and lab supervisors who will analyze samples for study results.
Primary Purpose: Treatment
Official Title: Novel Combination Therapy for Osteoporosis in Men
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : June 30, 2023
Estimated Study Completion Date : June 30, 2024

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Osteoporosis

Arm Intervention/treatment
Experimental: teriparatide (TPTD) + the calcimimetic cinacalcet
Combination arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a 30-mg tablet of cinacalcet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
Drug: Teriparatide or human parathyroid hormone (PTH) 1-34
Teriparatide or PTH 1-34 is a 34 amino acid peptide derived by recombinant DNA technology from the authentic sequence of human parathyroid hormone. It is given by subcutaneous injection in the dosage of 20 micrograms per day in the trial in both treatment arms for the 48 weeks or 11 months of the trial.
Other Name: Forteo

Drug: Cinacalcet
This drug is an orally active calcimimetic (drug that activates Ca-sensing receptors on target cells) that will be given daily orally to the men randomized to the Experimental Treatment Arm (#1). Cinacalcet tablets will be given simultaneously with the injection of PTH(1-34) or teriparatide. Cinacalcet will be given only once daily but given every single day of the trial starting with the Randomization Visit for the duration of 48 weeks or 11 months of the trial.
Other Name: Sensipar

Dietary Supplement: Calcium citrate tablet
Ca citrate supplements (forms 200 or 250 mg elemental Ca/oral tablet) will be used in the study. Each subject will have average dietary Ca intake quantified by a Food Frequency Questionaire. Each subject will take sufficient Ca citrate supplements to make the total Ca intake equal ~1000 mg per day (diet+supplements). Ca supplements will be spread out during the day so that any amount of supplements over 500 mg will be taken at 2 different time-points. Ca citrate supplements will be sourced by our research pharmacist will be of high-quality and consistency. Ca supplements will be started at Screening Visit 2 and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily Ca supplements at the same dose and times as during the run-in period. That daily dosing will continue from day of Randomization through the end of 48 weeks or 11 months of the trial.
Other Name: Calcium citrate supplement

Dietary Supplement: Vitamin D3
Subjects will be given 1000 IU vitamin D3 in tablet form to be taken orally once a day at any time during the day. Vitamin D3 supplements will be sourced by our research pharmacist and supplements selected for use in the trial will be of high quality and consistency. Vitamin D3 supplements will be started at Screening Visit 2 in the trial and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily vitamin D3 supplements at the same dose and timing as during the run-in period. That daily dosing will continue from the day of Randomization Visit through to the end of the 48 weeks or 11 months of the trial.
Other Name: Cholecalciferol

Placebo Comparator: teriparatide (TPTD) + placebo
Monotherapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a placebo tablet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
Drug: Teriparatide or human parathyroid hormone (PTH) 1-34
Teriparatide or PTH 1-34 is a 34 amino acid peptide derived by recombinant DNA technology from the authentic sequence of human parathyroid hormone. It is given by subcutaneous injection in the dosage of 20 micrograms per day in the trial in both treatment arms for the 48 weeks or 11 months of the trial.
Other Name: Forteo

Drug: placebo tablet
The placebo tablet in the trial will be purchased from Consolidated Midland Corporation in Brewster, NY. Each white tablet contains Lactose, Stearic Acid and Magnesium Stearate (330 mg total). Subjects randomized to the placebo arm or Placebo - Arm #2 - will take one tablet orally at the same time as he injects the teriparatide each day. Placebo tablets will be given only once daily but given every single day of the trial starting with the Randomization Visit for the duration of 48 weeks or 11 months of the trial.
Other Name: placebo

Dietary Supplement: Calcium citrate tablet
Ca citrate supplements (forms 200 or 250 mg elemental Ca/oral tablet) will be used in the study. Each subject will have average dietary Ca intake quantified by a Food Frequency Questionaire. Each subject will take sufficient Ca citrate supplements to make the total Ca intake equal ~1000 mg per day (diet+supplements). Ca supplements will be spread out during the day so that any amount of supplements over 500 mg will be taken at 2 different time-points. Ca citrate supplements will be sourced by our research pharmacist will be of high-quality and consistency. Ca supplements will be started at Screening Visit 2 and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily Ca supplements at the same dose and times as during the run-in period. That daily dosing will continue from day of Randomization through the end of 48 weeks or 11 months of the trial.
Other Name: Calcium citrate supplement

Dietary Supplement: Vitamin D3
Subjects will be given 1000 IU vitamin D3 in tablet form to be taken orally once a day at any time during the day. Vitamin D3 supplements will be sourced by our research pharmacist and supplements selected for use in the trial will be of high quality and consistency. Vitamin D3 supplements will be started at Screening Visit 2 in the trial and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily vitamin D3 supplements at the same dose and timing as during the run-in period. That daily dosing will continue from the day of Randomization Visit through to the end of the 48 weeks or 11 months of the trial.
Other Name: Cholecalciferol




Primary Outcome Measures :
  1. Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on lumbar spine BMD in men with low bone mass [ Time Frame: 48 weeks ]
    Hypothesis 1a proposes that BMD responses to combined TPTD+cinacalcet are greater than those induced by TPTD+PBO. LS BMD typically responds quickly and robustly to TPTD and is the 1o endpoint of the trial. DXA measurements will be performed and analyzed by standard protocols at baseline and at the end of the trial. Subjects will be treated for 11 months (48 weeks). All subjects will receive Ca and vitamin D3 supplements throughout the trial. The percentage change in LS BMD from baseline to 48 week/11 months of treatment will be the variable/endpoint that is calculated.


Secondary Outcome Measures :
  1. Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on serum P1NP in men with low bone mass [ Time Frame: 48 weeks ]
    Hypothesis 1b proposes that serum P1NP (N-terminal pro-peptide of type 1 collagen), a highly sensitive marker of bone turnover and specifically of bone formation, will increase to a greater extent in men treated with TPTD+cinacalcet vs TPTD+PBO. Serum P1NP is the best validated biomarker of TPTD action and responds rapidly and robustly to anabolic therapy. This secondary endpoint will be assessed at the 3 month/12 week visit in the fasting state on morning lab tests (prior to study drug administration). The endpoint is a blood test of bone formation marker comparing results from Day 1/Randomization Visit to Study Visit at 3 months/12 weeks. The percentage change in this bone formation marker will be the variable that will constitute this secondary endpoint.

  2. Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on femoral neck BMD in men with low bone mass [ Time Frame: 48 weeks ]
    Hypothesis 1a also proposes femoral neck BMD responses to combined TPTD+cinacalcet are greater than those induced by TPTD+PBO. FN BMD responses tend to be smaller than LS BMD responses to TPTD and this aim will test whether the combination therapy (CaSR activation + PTH-R activation) will produce larger BMD responses at the FN site in men with low BMD. The percentage change in FN BMD from baseline to 48 week/11 months of treatment will be the variable/endpoint that is calculated.


Other Outcome Measures:
  1. Pharmacodynamic responses to TPTD+cinacalcet and to TPTD+PBO in men with low bone mass [ Time Frame: 48 weeks ]
    This outcome has two components testing 2 hypotheses. Hypothesis 2a proposes that serum Ca levels do not decrease to >5% below lower limits of normal in response to study drugs. Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg/24 hrs in men treated chronically with study drugs. Hypothesis 2a will be in 2 ways: (1) PD testing done at Randomization Visit where serial blood samples (for serum Ca, PTH, phosphate, albumin) will be done at time 0, 2, 4, and 8 hrs after study drugs are given (acute PD). (2) Throughout the study PD responses will be assessed by measuring serum Ca levels (and albumin, phosphate, PTH) at every visit. This will assess chronic changes in serum minerals and PTH with 48 week/11 month treatment (chronic PD). 24 hr urine Ca is assessed at baseline and at defined times in full trial (chronic PD). Urine Ca is expected not to exceed 350 mg during the study. Each time-point of assessment will be compared to baseline values.



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Ages Eligible for Study:   60 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • DXA BMD T-score < or = -2.0 at either lumbar spine (LS), femoral neck (FN) or total hip (TH) sites; or DXA BMD T-score < or = -1.5 with at least one additional important clinical risk factor for osteoporotic fracture [e.g., fragility fracture after age 50 years; parental history of hip fracture; history of hypogonadism, prior glucocorticoid therapy (>3 months prior), current smoking, prevalent vertebral fracture(s), or prior hyperthyroidism on stable treatment]
  • At least 2 LS vertebral levels with reliable BMD values (i.e., at least 2 without compression or hardware)

Exclusion Criteria:

  • Metabolic bone disease other than osteoporosis (e.g., Paget's disease, hyperparathyroidism)
  • Any osteoporosis drug therapy within 12 months; any prior course of TPTD for > or = 3 months; any history of IV bisphosphonate therapy; oral bisphosphonate therapy exceeding 3 months in past 2 years; oral bisphosphonate treatment exceeding 2 years ever; or use of denosumab (within the past 3 years or > 3 or = injections ever).
  • Oral glucocorticoid use (> or = 5 mg prednisone) taken within 3 months prior to enrollment
  • Hypercalcemia (albumin-corrected serum [Ca] >10.2 mg/dL), hypocalcemia (albumin-corrected serum [Ca] <8.8 mg/dL), elevated intact PTH level, or hypercalciuria (urinary Ca >300 mg/24 hours) at screening
  • 25 OH vitamin D levels <20 ng/ml or >80 ng/ml at screening
  • Estimated glomerular filtration rate < 30 ml/min (chronic kidney disease (CKD) stage 4 or 5)
  • Cancer within past 5 years except for non-melanomatous skin cancers
  • History of skeletal radiation, prior history of osteosarcoma or bone metastases
  • Substance abuse (>3 drinks/day), liver disease or impaired liver function (abnormal liver function tests defined as greater than 3 times the upper limit of normal), known cirrhosis, malabsorption
  • Poorly controlled diabetes (A1c >9.0%) or current thiazolidinedione therapy
  • Drugs metabolized through CYP2D6 (e.g., flecainide, tricyclic antidepressants) and strong inducers or inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole)
  • Testosterone therapy with dose change within last 12 months; or androgen deprivation therapy within 12 months
  • Thyrotropin (TSH) level < 0.01
  • Congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia
  • Hypersensitivity to teriparatide or any excipients in Forteo
  • Use of other Ca-lowering drugs (e.g., calcitonin, bisphosphonates, denosumab)
  • Moderate to severe hepatic impairment
  • High risk for active urolithiasis, defined as having passed a kidney stone clinically within the last 5 years
  • Upper gastrointestinal (GI) bleeding with a history of a clinical episode of upper GI bleeding within last 10 years that was note definitively treated by a surgical procedure
  • Orthostatic hypotension or a known history of orthostatic hypotension documented in the chart or provided by the patient upon clinical history-taking
  • Impaired cardiac function either diagnosed symptomatic heart failure requiring medical therapy

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03994172


Contacts
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Contact: Dolores M Shoback, MD (415) 221-4810 ext 23336 dolores.shoback@va.gov
Contact: Anne L Schafer, MD (415) 221-4810 ext 4895 Anne.Schafer@va.gov

Locations
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United States, California
San Francisco VA Medical Center, San Francisco, CA Not yet recruiting
San Francisco, California, United States, 94121
Contact: Heather Freasier, MS RD    415-379-5518    heather.freasier@va.gov   
Contact: Dolores M Shoback, MD    (415) 221-4810 ext 23336    dolores.shoback@va.gov   
Principal Investigator: Dolores M. Shoback, MD         
Sponsors and Collaborators
VA Office of Research and Development
University of California, San Francisco
Investigators
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Principal Investigator: Dolores M. Shoback, MD San Francisco VA Medical Center, San Francisco, CA

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Responsible Party: VA Office of Research and Development
ClinicalTrials.gov Identifier: NCT03994172     History of Changes
Other Study ID Numbers: ENDB-012-17F
1 IO1 CX001514-01A2 ( Other Grant/Funding Number: Department of Veterans Affairs )
First Posted: June 21, 2019    Key Record Dates
Last Update Posted: July 1, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: Individual Participant Data (IPD) sets will be shared. All IPD collected during the trial after de-identification will be shared. The types of Supporting Information that will be shared (in addition to IDP and Data Dictionaries) include Study Protocol, Statistical Analysis Plan, Informed Consent Form, Clinical Study Report, and Analytic Code. The data will be available 6 months after the publication of the study, with no end date, and will be available to anyone who wishes to access the data and provides a methodologically sound proposal. The types of analyses that are planned in that proposal will be reviewed by the research study team of investigators, consultants and collaborators. To gain access to the data, requesting investigators will need to sign a Data Use Agreement.
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Analytic Code
Time Frame: Six (6) months after the trial data are published and then indefinitely afterwards
Access Criteria: All IDP data after deidentification collected during the trial will become available 6 months after the trial publication is published. This is a 5-year project commencing approximately July 1, 2019, and will continue through June 30, 2024, until all subject level data is collected and the trial interventions completed. Once study data are fully analyzed and published, then 6 months later, the IPD data sets and IPD Supporting Information will be available to other investigators.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by VA Office of Research and Development:
male osteoporosis
anabolic therapy
teriparatide
calcimimetic
calcium-sensing receptor
PTH receptor
bone formation

Additional relevant MeSH terms:
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Osteoporosis
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Vitamin D
Ergocalciferols
Calcium, Dietary
Cholecalciferol
Teriparatide
Vitamins
Citric Acid
Sodium Citrate
Calcium
Parathyroid Hormone
Cinacalcet
Hormones
Micronutrients
Nutrients
Growth Substances
Physiological Effects of Drugs
Bone Density Conservation Agents
Calcium-Regulating Hormones and Agents
Hormones, Hormone Substitutes, and Hormone Antagonists
Anticoagulants
Calcium Chelating Agents
Chelating Agents
Sequestering Agents
Molecular Mechanisms of Pharmacological Action
Calcimimetic Agents