Ignite Creation Date:
2024-05-06 @ 1:19 PM
Last Modification Date:
2024-10-26 @ 1:12 PM
Study NCT ID:
NCT03994172
Status:
ACTIVE_NOT_RECRUITING
Last Update Posted:
2024-07-12
First Post:
2019-06-18
Brief Title:
Novel Combination Therapy for Osteoporosis in Men
Sponsor:
VA Office of Research and Development
Organization:
VA Office of Research and Development
Study Overview
Official Title:
Novel Combination Therapy for Osteoporosis in Men
Status:
ACTIVE_NOT_RECRUITING
Status Verified Date:
2024-08
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
Osteo-Men
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 PTH1-34 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 TPTDcalcimimetic cinacalcet in men will produce greater bone forming responses than PTH-R activation alone TPTDplacebo 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 TPTDcinacalcet vs TPTDplacebo 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 TPTDcinacalcet compared to men who get TPTDplacebo 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
Detailed Description:
NOVEL COMBINATION THERAPY FOR OSTEOPOROSIS IN MEN
1 Background for the Study
What Is the Risk of Osteoporotic Fractures in Men and Why Do Men Lose Bone Mass Osteoporosis is a neglected condition in men Yet men sustain approximately 30 of the 15 million fractures that occur annually in the US Fractures are expensive Estimated costs are at least 20 billion annually This figure will no doubt rise substantially as the population ages Plus these costs do not take into account the personal and societal burden of fractures especially hip fractures One in 6 men will sustain a hip fracture by the time he reaches age 90 years A man who fractures a hip at any age has greater disability following that fracture and is much less likely to regain his ability to walk and to live independently afterward Men also have a greater risk of dying from the complications of hip fractures Overall one-year mortality for patients who sustain a hip fracture is 20 However mortality in men with hip fractures is staggeringly high at 375 in the first year
The pathophysiology of bone loss in aging men differs in important ways from postmenopausal osteoporosis Age-related bone loss in men begins in the 6th decade with nutritional and hormonal abnormalities playing important roles Contributing factors include decreased intestinal Ca absorption vitamin D deficiency or insufficiency and secondary 2o hyperparathyroidism HPT Testosterone levels decline with age in men and as they do estradiol levels also fall Considerable evidence supports an important role for estradiol in maintaining bone mass in men as well as women Men lose both trabecular and cortical bone mass with age Trabecular bone thins out in men rather than perforates as it does in women and excessive cortical bone remodeling is a dominant force in older men In men periosteal bone apposition does not keep pace with endosteal resorption and the bones weaken With minimal trauma fragility fractures may result Thus reduced bone formation is a key mechanism underlying bone loss in men more so than the high rates of bone resorption seen in postmenopausal estrogen deficiency For these reasons anabolic regimens that enhance bone formation may achieve better clinical outcomes in men compared to commonly used antiresorptive agents This trial will test a novel anabolic combination therapy in men
How Effective Are Current Treatments for Osteoporosis in Men Several agents have been Food and Drug Administration FDA-approved to treat osteoporosis in men bisphosphonates denosumab and teriparatide TPTD or parathyroid hormone PTH 1-34 In trials enrolling men these agents were shown to increase bone mineral density BMD by dual energy Xray absorptiometry DXA at key skeletal sites quantitatively similar to their effects in postmenopausal women In only a few appropriately powered studies there was a reduction in incident vertebral fractures in men at high risk andor those on androgen deprivation therapy
Intermittent injections of TPTD are appealing as a treatment for osteoporosis in men because the agent has potent anabolic actions TPTD increases bone formation reflected by enhanced biochemical markers of osteoblast OB activity such as N-terminal propeptide of type 1 collagen P1NP and bone specific alkaline phosphatase BSAP in the blood and by direct histomorphometric quantification of bone formation and mineral apposition rates TPTD also improves the microarchitecture of bone by micro-CT trabecular thickness and connectivity and increases the maturation or number of circulating osteogenic precursors and stem cells in blood in postmenopausal women TPTD in vitro stimulates the proliferation of mesenchymal stem cells and their commitment to the OB lineage as osteoprogenitors PTH 1-34 also increases differentiation of early OBs and matrix production blocks apoptosis of OBs and osteocytes and reduces production of the Wnt inhibitor sclerostin by osteocytes The anabolic actions of PTH treatment within a defined time-frame 18 to 24 months in humans -- called the anabolic window -- improve bone strength and ultimately reduce spine and nonvertebral fractures Over time however PTH stimulates receptor activator of nuclear factor kappa B ligand RANK-L production by early OB lineage cells and RANK-L enhances osteoclast OC production This increases bone resorption which limits further gains in BMD with PTH The challenge in designing optimal treatment regimens with PTH is maximizing its anabolic activity while taming its catabolic effects on bone
Clinical trials with TPTD recombinant human PTH 1-34 or synthetic human PTH 1-34 in men are limited to a few studies with small numbers of men Orwoll and colleagues randomized 437 men into 3 groups placebo PBO vs 20 the dose subsequently FDA-approved or 40 ug TPTD daily However they completed only an average of 11 months on treatment Kurland and colleagues randomized 23 men to synthetic PTH 1-34 400 IU or 25 ugday N10 or PBO N13 for 18 months Finkelstein and colleagues as part of a combination study randomized 27 men to synthetic PTH 1-34 for 24 months 37 ugday Thus that study used twice the approved dose of PTH 1-34 Walker and colleagues randomized men to risedronate 35 mgweek N10 TPTD 20 ugday N9 or the combination N10 for 18 months In these studies BMD rose by 6-14 at the lumbar spine and by 2-4 at femoral neck with 11-18 months treatment with 20 or 25 ug PTH 1-34day Higher doses of PTH 1-34 37 or 40 ugday produced even greater responses at both sites 2-3 fold more This indicates that stronger anabolic effects are feasible to achieve in men within these short time-frames However these doses are less tolerated and the investigators do not plan to use them Rather the trial proposed will use the FDA-approved dose of TPTD 20 ugd by daily subcutaneous injection
Combination studies of PTH 1-34 with alendronate or TPTD with risedronate did not convincingly show synergistic effects on BMD in men A trial combining TPTD and denosumab showed additive effects of the combination but it was done in women Several important questions about TPTD treatment in men have never been addressed Among them can TPTD be advantageously combined with another bone-active drug that has a similar or a different mechanism of action Investigators in the field only know that adding PTH 1-34 to alendronate in men does not produce additive effects This trial will test the hypothesis that concurrent CaSR activation by calcimimetic synergizes with PTH-R activation by TPTD to produce greater anabolic effects in men reflected by changes in BMD and bone turnover markers BTMs compared to TPTD alone This is a novel combination therapy that is well-supported in preclinical studies
2 Scientific Premise for the Planned Intervention This is a first in human study of a combination therapy for osteoporosis Both of the drugs that will be used in the trial have been FDA-approved for many years and have been used in the clinic in hundreds of thousands of patients worldwide TPTD for the treatment of osteoporosis in women and men and cinacalcet for the treatment of various forms of HPT in women and men The two agents to be used in the trial have not been as yet tested in the combination format that will be done in this study
Summarized below are preclinical data from young 12-week old and elderly 12-month old male and female mice
Preclinical Studies Combined PTH1-34 and Calcimimetic Produce Marked Anabolic Effects on Bone in Mice Both extracellular Ca-sensing receptors CaSRs and PTH receptors PTH-Rs play central roles in the control of bone remodeling In conditional or tissue-specific knockout mice CaSRs have been shown to play key roles in skeletal development and in OB and osteocyte function by several groups Such work supports the idea that high extracellular Ca Cae acting through CaSRs is an anabolic pathway in bone akin to intermittent PTH 1-34 stimulation of PTH-R signaling in bone Several groups have found that direct CaSR activation in OC lineage cells reduced their survival gene expression and resorptive function This suggested that enhanced OB and suppressed OC function might be accomplished through activation of CaSRs in different bone cell populations
Based on this work in mice and the known role of PTH peptides as bone anabolic agents in humans studies were done in mice to test the hypothesis that concurrent activation of PTH-Rs and of CaSRs has synergistic effects on bone mass Adult male mice given intermittent subcutaneous SC injections of PTH1-34 40-80 ugkg and the calcimimetic NPS-R568 20 umolekg for 4-6 weeks showed dramatic synergistic anabolic effects on bone mass and strength PTH 1-34 injections alone significantly increased trabecular Tb bone mass Tb bone volumetissue volume BVTV by micro-CT in the distal femur as well as Tb thickness TbTh p005 Co-injections of PTH 1-34 and NPS-R568 produced significantly greater effects on Tb BVTV and TbTh by 21 p001 while NPS-R568 injections alone had no effect These are large effects on bone mass as determined by highly sensitive methods - micro CT and bone histomorphometry The latter is the gold-standard for testing the effects of an intervention on dynamic bone metabolic processes This combination therapy also produced bone microarchitectural changes more plate-like trabeculi compatible with mechanically stronger bone
Cortical Ct bone is typically less affected by PTH 1-34 treatment However in these experiments when Ct bone at the tibiofibular junction TFJ was assessed by micro-CT it was clear that combined injections of PTH 1-34 and NPS-R568 produced dramatic increases in CtTV CtBV and CtTh of 8-10 p005 Thus this work demonstrated clear anabolic synergy of concomitant PTH-R and CaSR activation on both Tb and Ct bone in adult male mice - findings potentially clinically significant and highly relevant to the proposed trial Similar and dose-dependent increases were seen in Tb bone of the L5 vertebrae in BVTV TbTh and Tb number N p005 or p001 and in their Ct bone at the TFJ CtTV CtBV and CtTh p005 in elderly female mice
Dynamic histomorphometry on bone biopsy specimens in the mice supported these results Daily injections for 6 weeks of TPTD alone induced substantial bone formation by fluorescent tetracycline labelling from Ct bone sections Bone formation was substantially augmented by co-administration of calcimimetic NPS R568 Quantitative analyses of Tb and Ct bone parameters N12 micegroup supported the micro-CT data indicating robustly strong increases in bone mass with this combination By mechanical testing of the mouse femurs bone strength was tested and the bones were found to be stronger greater energy to failure in the male mice treated with combined PTHNPS-R568 vs PTH 1-34vehicle
3 Study Rationale Osteoporosis and fracture-related disability are important health problems in older men Fractures increase mortality Men who fracture their hips have twice the mortality of women sustaining those same hip fractures Several drugs are approved to treat osteoporosis in men bisphosphonates denosumab and teriparatide TPTD or PTH1-34 but there have been little insight as to how to use them most effectively TPTD has great appeal for treating osteoporosis in men because it substantially improves bone mass rebuilds the microarchitecture improves bone strength and reduces fractures Little is known about the best ways to employ TPTD in the treatment of male osteoporosis Should it be used only as monotherapy or does concurrent or sequential use with other agents lead to the greatest benefit The proposed clinical trial is an effort to test a novel combination therapy for osteoporosis in men based on exciting preclinical findings in mice It is known that TPTD achieves its anabolic effects by stimulating PTH-Rs in cells of the OB lineage Calcimimetics mimic the effects of high extracellular calcium concentrations Cae by activating CaSRs expressed in many cell types including OBs and OCs in bone
ASpecific Aims and Hypotheses Tested To address the hypothesis that concurrent CaSR and PTH-R activation produces synergistic anabolic effects on bone a double-blind PBO-controlled trial in 48 men with low BMD testing a novel combination regimen will be performed Older male Veterans with low BMD by DXA will be randomized to 2 treatment arms TPTDcinacalcet vs TPTDPBO Efficacy endpoints will be changes in BMD by DXA and the bone turnover marker BTM P1NP Aim 1 Pharmacodynamic PD effects of the combination regimen vs monotherapy will be profiled serum Ca PTH and safety confirmed Aim 2 A subset of 24 patients 12treatment arm will undergo detailed acute 8 hr PD assessments and clinical monitoring at the UCSF CRC Clinical Research Center Safety will be assessed in all trial subjects with serum Ca and 24-hour urinary Ca monitoring and with adverse event AE and clinical assessments Although both drugs used in this trial are FDA-approved TPTD 20 ugday for osteoporosis cinacalcet 30 mgday for HPT an IND Investigational New Drug application is in place to give this drug combination
BStudy Aims and Hypotheses AIM 1 To determine the effects of treatment with TPTDcinacalcet compared to TPTDPBO on BMD and bone metabolism in men with low bone mass by assessing responses in lumbar spine LS BMD primary endpoint and femoral neck FN BMD and levels of P1NP
There are 2 hypotheses tested in this aim Hypothesis 1a proposes that BMD responses to combined TPTDcinacalcet are greater than those induced by TPTDPBO LS BMD typically responds quickly and robustly to TPTD and is the 1o endpoint of the trial Changes in FN BMD a site often slower to respond and with smaller magnitude are a 2o endpoint DXA measurements will be performed and analyzed as described below Subjects will be treated for 11 months 48 weeks All subjects will receive Ca and vitamin D3 supplements throughout the trial Hypothesis 1b proposes that bone formation marker P1NP increases to a greater extent with combined TPTDcinacalcet vs TPTDPBO P1NP is the best validated biomarker of TPTD action and responds rapidly and robustly to anabolic therapy the change in P1NP at 3 months 12 weeks after initiation of treatment is a key 2o endpoint for the study
AIM 2 To determine the pharmacodynamic PD responses to study drug administration in men with low bone mass by assessing acute and chronic changes in the serum Ca and plasma intact PTH after drug administration and changes in urinary Ca excretion
There are 2 hypotheses tested in the PD studies in this aim which is focused on establishing physiologic responses and confirming safety with this combination therapy Hypothesis 2a proposes that the serum Ca does not fall to 5 below the lower limits of the normal range in response to the administration of study drugs After randomization subjects will initiate dosing with the 2 study drugs First baseline sampling pre-study drug will be done and then subjects will have blood collected for serum Ca albumin and PTH at specific time-points in the 8 hours after study drugs are administered As is clear from the literature on PTH actions in vivo TPTD tends to raise serum Ca while cinacalcet is expected to lower intact PTH and thereby serum Ca usually transiently It is anticipated that the effects of these 2 drugs known to act over similar time-courses in humans will tend to offset each other so that the serum Ca remains stable and within the normal range in subjects taking the combination TPTDcinacalcet In general the majority of patients taking TPTD and the majority of those receiving cinacalcet should experience offset of drug effects well before 24 hours have elapsed post-dosing Based on these kinetics it is not expected that combined treatment will produce major steady-state changes in serum Ca At the very least it is expected that any serum Ca lowering will be modest and transient and steady-state levels will not drop 5 below the lower limit of the normal range This will be carefully assessed both acutely in the PD study in 24 subjects 12treatment arm and chronically by examining pre-dose serum Ca over the full study in all subjects Intact PTH will be monitored as an exploratory endpoint since serum PTH levels may fall with chronic cinacalcet treatment Determining changes in endogenous PTH secretion may be important for fully understanding the PD of concurrent TPTDcinacalcet therapy
Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg24 hours in subjects receiving study drugs This parameter will be carefully studied throughout the trial for these reasons First TPTD may raise urinary Ca because of increased gut Ca absorption due to increased 125OH2 vitamin D and enhanced Ca mobilization from bone direct PTH action Both effects increase the filtered load of Ca which can raise urinary Ca Second calcimimetics by stimulating renal CaSRs may also raise urinary Ca levels Hypothesis 2b is predicated on the observation that men treated with TPTD alone did not excrete 350 mg Ca24 hours according to prior clinical trial data In addition prior studies in patients with 1o HPT did not show significant hypercalciuria due to cinacalcet However data on urinary Ca in normal subjects taking calcimimetics are scant If chronic hypercalciuria results from the combination therapy there is potential for consequences renal stones possibly renal insufficiency that will be key to know about Thus urinary Ca assessments throughout the study are critical safety endpoints
CPrimary and Secondary Objectives As primary objective the study will examine the effects on LS BMD by DXA of treatment with the combination of TPTD PTH 1-34 placebo vs TPTD oral calcimimetic cinacalcet in men with low bone mass or osteoporosis
The study has two secondary objectives 1 assess the effects of combination of TPTD PTH 1-34 placebo vs TPTD oral calcimimetic cinacalcet on FN BMD by DXA in men with low bone mass or osteoporosis and 2 assess the effects of the combination of TPTD PTH 1-34 PBO vs TPTD oral calcimimetic cinacalcet on the bone formation marker serum P1NP in men with low bone mass or osteoporosis
A safety assessment will include determining a acute and chronic changes in the concentrations of serum Ca Ca and plasma intact PTH after administration of study medications in both treatment arms in an 8 hour PD study and b changes in 24 hour urinary Ca excretion over full 11 month trial with both treatment regimens
4 Study Design and Protocol
ASubjects There will be 48 men randomized to one of two treatment arms TPTD PBO tablet N24 or TPTD cinacalcet tablet N24 Men of all ethnic and racial groups will be encouraged to participate The DXA scan done at screening will be used to determine whether or not a man meets BMD criteria for enrollment into the study
BInclusion and Exclusion Criteria for Subjects - described elsewhere in the application
CStudy Drugs and Supplements Teriparatide TPTD or PTH 1-34 which will be obtained from commercial sources and given at 20 mcg daily by SC injection Cinacalcet or sensipar an oral calcimimetic will be given at the dose 30 mg daily orally
The PBO control will be a purchased placebo tablet that will be packaged in exactly the same manner as cinacalcet Supplements in the form of Ca citrate tablets 200 or 500 mg tablets will be given in both treatment arms to subjects along with vitamin D3 1000 International Units by mouth daily Ca supplements will be adjusted along with an assessment of dietary Ca intake to reach a total of 1000 mg elemental Ca per day
DStudy Measurements Several types of measurements will be made in the course of the trial
1 BMD will be measured at the LS hip and radius by DXA at the UCSF CTSI CRC Trabecular bone score TBS will also be determined from the data collected during the DXA assessment of the lumbar spine using commercially available software applications available at the investigators center
2 Biochemical markers of bone turnover BTMs and vitamin D metabolites will be measured during the study visits including the following serum P1NP serum C-telopeptide CTX bone specific alkaline phosphatase BSAP osteoprotegerin OPG RANK-L and 125 OH2 vitamin D
3 Dietary Ca intake will be assessed by the Block Food Frequency Questionnaire
4 There will be PD testing during the study This will include assessing acute changes in the serum levels of Ca albumin phosphate and PTH during the acute administration of the study drugs during an 8-hour PD test in the clinic at the Randomization Visit of the study determining chronic changes in the serum levels of calcium and PTH during the entire study with the administration of the study drug combinations 11 months of the trial studying chronic changes in the urinary calcium at study visits during the full trial
5 In exploratory studies peripheral blood mononuclear cells PBMCs will be collected by blood sampling of participants and those samples fractionated for cells of the OB and OC lineage to determine whether the two treatment interventions alter the levels and properties gene expression markers of the circulating populations of these cells
EStudy Duration and Study Visits Subjects will be on study for approximately 12-13 months Screening will be conducted at 2 separate visits This will be followed by a run-in period of 4 weeks for eligible subjects The intervention period will be 11 months 48 weeks in duration
Screening will be done through a telephone call to initiate contact describe the study and set up a visit to achieve informed consent and to do the screening DXA scan There are two Screening Visits the first will involve obtaining the DXA scan and the second will involve lab testing a complete medical history and physical exam to be performed The run-in period during which the participant takes only calcium and vitamin D supplements for 4 weeks will follow
The Randomization Visit will involve lab testing and in 1224 subjects in each arm an 8-hour PD Study Subjects will be randomized to one of the study treatment arms and taught to take the daily injections and the study medication tablets cinacalcet vs PBO At week 1 subjects will have lab testing done and a telephone visit Thereafter at Weeks 4 8 12 20 24 36 and 48 there will be lab testing of blood and urine assessment of adverse events and clinical followup done At the final visit Week 48 approximately 11 months a followup DXA scan will be done
FTimeline of main study procedures and interventions Momonth
Screening Visit 1
-Informed consent DXATBS
Screening Visit 2
-History physical exam vital signs screening labs blood urine food frequency questionnaire AE concomitant medications pen teaching supplements dispensed
Randomization Visit -PD study vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 1 Visit
-Lab tests AE concomitant medications Cavitamin D intake check
Week 4 1 Mo Visit -Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 8 2 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 12 3 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 20 5 Mo Visit -Vital signs labs blood AE concomitant medications pen teaching supplements and study drugs dispensed extra blood collected Cavitamin D intake check
Week 24 6 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 36 9 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 48 11 Mo Visit
-DXA TBS history physical exam vital signs labs blood urine AE concomitant medications extra blood and PBMCs collected Cavitamin D intake check
5Study Analysis
Statistical Analysis Plan
Statistics will include descriptive as well as analytic approaches The intention-to-treat ITT approach will be used with all randomized men included in the analysis Complete follow-up data will be collected on every randomized subject regardless of adherence 2o per-protocol analyses will be done limited to those who remained on medication and those with complete data All statistical testing will be performed at nominal 005 level without adjustments for multiple comparisons
Analysis of Primary Endpoint
To determine the effects of 11 months of treatment with TPTDcinacalcet compared to TPTDPBO on LS BMD primary endpoint Testing the 1o hypothesis for the effect of the 2 treatment arms on the change in LS BMD will use a t-test with a two-sided significance level of 005 The extent of missing data will be reported in all statistical analyses Overall missing data rates are expected to be low since the investigators will make every attempt to obtain BMDs at 11 months for all men regardless of medication use 1o analyses will be unadjusted Using standard statistical methods and means and SDs from published TPTD studies the effect size true difference in means between treatment groups that can be detected based on a t-test comparison between treatment groups of the change in LS BMD with a fixed sample size of 24group was calculated Even if 20 of the subjects were lost to follow-up and did not contribute 11-month LS BMD data with a sample size of 40 the study is powered to detect a between-group difference as small as 40 A difference between treatment regimens of 4 eg mean LS BMD increase in TPTDPBO of 5 vs 9 increase in the combination group would be an effect size for BMD in the range that would be clinically promising and support pursuing further studies of this combination therapy for osteoporosis
Analysis of Secondary Endpoints
To determine the effects of 11 months of treatment with TPTDcinacalcet compared to TPTDPBO on FN BMD and levels of the bone formation marker P1NP secondary endpoints
A similar approach will be taken for FN BMD and for the logarithm of the P1NP change as will be taken for the primary endpoint above On an exploratory basis changes in TBS from baseline to study end will be analyzed as BMD is All hypotheses will be tested at the nominal 005 2-sided significance level with no formal adjustment for multiple comparisons In the analysis of 2o outcomes and in other 2o analyses it is recognized that this might increase type 1 error rates due to multiple testing To alleviate that concern 1o and 2o endpoints will be clearly distinguished as well as exploratory analyses Consistency among multiple endpoints will be looked and caution will be exercise in interpreting marginally significant findings particularly unexpected results not motivated by a priori hypotheses The extent of missing data will be reported in all statistical analyses Overall missing data rates are expected to be low since every attempt will be made to obtain BMDs at 11 months and P1NP at 3 months for all men regardless of medication use 1o analyses will be unadjusted
This study has 80 power with an alpha005 to detect a between-group difference in change in FN BMD as small as 35 Since effects of TPTD on FN BMD in short-term studies are small it is recognized that 35 may be an ambitious difference between treatments for hip BMD However the point estimates may give an indication of whether the combination has superior effects on BMD at the hip and help investigators to plan future studies of this combination
The distribution of P1NP change is non-Gaussian in multiple studies requiring log transformation log ratio and back-transformation for presentation Using data from the PaTH Parathyroid Hormone and Alendronate for Osteoporosis trial of the 3-month change in P1NP the back-transformed mean change 95 CI was 148 117 183 Based on the SD of the log ratio in PaTH a sample size of 40 20group assuming 20 non-completers will provide 80 power with alpha005 to detect a difference of 137 eg an increase from 148 to 285 between P1NP responses of men treated with TPTDcinacalcet vs TPTDPBO
1 Background for the Study
What Is the Risk of Osteoporotic Fractures in Men and Why Do Men Lose Bone Mass Osteoporosis is a neglected condition in men Yet men sustain approximately 30 of the 15 million fractures that occur annually in the US Fractures are expensive Estimated costs are at least 20 billion annually This figure will no doubt rise substantially as the population ages Plus these costs do not take into account the personal and societal burden of fractures especially hip fractures One in 6 men will sustain a hip fracture by the time he reaches age 90 years A man who fractures a hip at any age has greater disability following that fracture and is much less likely to regain his ability to walk and to live independently afterward Men also have a greater risk of dying from the complications of hip fractures Overall one-year mortality for patients who sustain a hip fracture is 20 However mortality in men with hip fractures is staggeringly high at 375 in the first year
The pathophysiology of bone loss in aging men differs in important ways from postmenopausal osteoporosis Age-related bone loss in men begins in the 6th decade with nutritional and hormonal abnormalities playing important roles Contributing factors include decreased intestinal Ca absorption vitamin D deficiency or insufficiency and secondary 2o hyperparathyroidism HPT Testosterone levels decline with age in men and as they do estradiol levels also fall Considerable evidence supports an important role for estradiol in maintaining bone mass in men as well as women Men lose both trabecular and cortical bone mass with age Trabecular bone thins out in men rather than perforates as it does in women and excessive cortical bone remodeling is a dominant force in older men In men periosteal bone apposition does not keep pace with endosteal resorption and the bones weaken With minimal trauma fragility fractures may result Thus reduced bone formation is a key mechanism underlying bone loss in men more so than the high rates of bone resorption seen in postmenopausal estrogen deficiency For these reasons anabolic regimens that enhance bone formation may achieve better clinical outcomes in men compared to commonly used antiresorptive agents This trial will test a novel anabolic combination therapy in men
How Effective Are Current Treatments for Osteoporosis in Men Several agents have been Food and Drug Administration FDA-approved to treat osteoporosis in men bisphosphonates denosumab and teriparatide TPTD or parathyroid hormone PTH 1-34 In trials enrolling men these agents were shown to increase bone mineral density BMD by dual energy Xray absorptiometry DXA at key skeletal sites quantitatively similar to their effects in postmenopausal women In only a few appropriately powered studies there was a reduction in incident vertebral fractures in men at high risk andor those on androgen deprivation therapy
Intermittent injections of TPTD are appealing as a treatment for osteoporosis in men because the agent has potent anabolic actions TPTD increases bone formation reflected by enhanced biochemical markers of osteoblast OB activity such as N-terminal propeptide of type 1 collagen P1NP and bone specific alkaline phosphatase BSAP in the blood and by direct histomorphometric quantification of bone formation and mineral apposition rates TPTD also improves the microarchitecture of bone by micro-CT trabecular thickness and connectivity and increases the maturation or number of circulating osteogenic precursors and stem cells in blood in postmenopausal women TPTD in vitro stimulates the proliferation of mesenchymal stem cells and their commitment to the OB lineage as osteoprogenitors PTH 1-34 also increases differentiation of early OBs and matrix production blocks apoptosis of OBs and osteocytes and reduces production of the Wnt inhibitor sclerostin by osteocytes The anabolic actions of PTH treatment within a defined time-frame 18 to 24 months in humans -- called the anabolic window -- improve bone strength and ultimately reduce spine and nonvertebral fractures Over time however PTH stimulates receptor activator of nuclear factor kappa B ligand RANK-L production by early OB lineage cells and RANK-L enhances osteoclast OC production This increases bone resorption which limits further gains in BMD with PTH The challenge in designing optimal treatment regimens with PTH is maximizing its anabolic activity while taming its catabolic effects on bone
Clinical trials with TPTD recombinant human PTH 1-34 or synthetic human PTH 1-34 in men are limited to a few studies with small numbers of men Orwoll and colleagues randomized 437 men into 3 groups placebo PBO vs 20 the dose subsequently FDA-approved or 40 ug TPTD daily However they completed only an average of 11 months on treatment Kurland and colleagues randomized 23 men to synthetic PTH 1-34 400 IU or 25 ugday N10 or PBO N13 for 18 months Finkelstein and colleagues as part of a combination study randomized 27 men to synthetic PTH 1-34 for 24 months 37 ugday Thus that study used twice the approved dose of PTH 1-34 Walker and colleagues randomized men to risedronate 35 mgweek N10 TPTD 20 ugday N9 or the combination N10 for 18 months In these studies BMD rose by 6-14 at the lumbar spine and by 2-4 at femoral neck with 11-18 months treatment with 20 or 25 ug PTH 1-34day Higher doses of PTH 1-34 37 or 40 ugday produced even greater responses at both sites 2-3 fold more This indicates that stronger anabolic effects are feasible to achieve in men within these short time-frames However these doses are less tolerated and the investigators do not plan to use them Rather the trial proposed will use the FDA-approved dose of TPTD 20 ugd by daily subcutaneous injection
Combination studies of PTH 1-34 with alendronate or TPTD with risedronate did not convincingly show synergistic effects on BMD in men A trial combining TPTD and denosumab showed additive effects of the combination but it was done in women Several important questions about TPTD treatment in men have never been addressed Among them can TPTD be advantageously combined with another bone-active drug that has a similar or a different mechanism of action Investigators in the field only know that adding PTH 1-34 to alendronate in men does not produce additive effects This trial will test the hypothesis that concurrent CaSR activation by calcimimetic synergizes with PTH-R activation by TPTD to produce greater anabolic effects in men reflected by changes in BMD and bone turnover markers BTMs compared to TPTD alone This is a novel combination therapy that is well-supported in preclinical studies
2 Scientific Premise for the Planned Intervention This is a first in human study of a combination therapy for osteoporosis Both of the drugs that will be used in the trial have been FDA-approved for many years and have been used in the clinic in hundreds of thousands of patients worldwide TPTD for the treatment of osteoporosis in women and men and cinacalcet for the treatment of various forms of HPT in women and men The two agents to be used in the trial have not been as yet tested in the combination format that will be done in this study
Summarized below are preclinical data from young 12-week old and elderly 12-month old male and female mice
Preclinical Studies Combined PTH1-34 and Calcimimetic Produce Marked Anabolic Effects on Bone in Mice Both extracellular Ca-sensing receptors CaSRs and PTH receptors PTH-Rs play central roles in the control of bone remodeling In conditional or tissue-specific knockout mice CaSRs have been shown to play key roles in skeletal development and in OB and osteocyte function by several groups Such work supports the idea that high extracellular Ca Cae acting through CaSRs is an anabolic pathway in bone akin to intermittent PTH 1-34 stimulation of PTH-R signaling in bone Several groups have found that direct CaSR activation in OC lineage cells reduced their survival gene expression and resorptive function This suggested that enhanced OB and suppressed OC function might be accomplished through activation of CaSRs in different bone cell populations
Based on this work in mice and the known role of PTH peptides as bone anabolic agents in humans studies were done in mice to test the hypothesis that concurrent activation of PTH-Rs and of CaSRs has synergistic effects on bone mass Adult male mice given intermittent subcutaneous SC injections of PTH1-34 40-80 ugkg and the calcimimetic NPS-R568 20 umolekg for 4-6 weeks showed dramatic synergistic anabolic effects on bone mass and strength PTH 1-34 injections alone significantly increased trabecular Tb bone mass Tb bone volumetissue volume BVTV by micro-CT in the distal femur as well as Tb thickness TbTh p005 Co-injections of PTH 1-34 and NPS-R568 produced significantly greater effects on Tb BVTV and TbTh by 21 p001 while NPS-R568 injections alone had no effect These are large effects on bone mass as determined by highly sensitive methods - micro CT and bone histomorphometry The latter is the gold-standard for testing the effects of an intervention on dynamic bone metabolic processes This combination therapy also produced bone microarchitectural changes more plate-like trabeculi compatible with mechanically stronger bone
Cortical Ct bone is typically less affected by PTH 1-34 treatment However in these experiments when Ct bone at the tibiofibular junction TFJ was assessed by micro-CT it was clear that combined injections of PTH 1-34 and NPS-R568 produced dramatic increases in CtTV CtBV and CtTh of 8-10 p005 Thus this work demonstrated clear anabolic synergy of concomitant PTH-R and CaSR activation on both Tb and Ct bone in adult male mice - findings potentially clinically significant and highly relevant to the proposed trial Similar and dose-dependent increases were seen in Tb bone of the L5 vertebrae in BVTV TbTh and Tb number N p005 or p001 and in their Ct bone at the TFJ CtTV CtBV and CtTh p005 in elderly female mice
Dynamic histomorphometry on bone biopsy specimens in the mice supported these results Daily injections for 6 weeks of TPTD alone induced substantial bone formation by fluorescent tetracycline labelling from Ct bone sections Bone formation was substantially augmented by co-administration of calcimimetic NPS R568 Quantitative analyses of Tb and Ct bone parameters N12 micegroup supported the micro-CT data indicating robustly strong increases in bone mass with this combination By mechanical testing of the mouse femurs bone strength was tested and the bones were found to be stronger greater energy to failure in the male mice treated with combined PTHNPS-R568 vs PTH 1-34vehicle
3 Study Rationale Osteoporosis and fracture-related disability are important health problems in older men Fractures increase mortality Men who fracture their hips have twice the mortality of women sustaining those same hip fractures Several drugs are approved to treat osteoporosis in men bisphosphonates denosumab and teriparatide TPTD or PTH1-34 but there have been little insight as to how to use them most effectively TPTD has great appeal for treating osteoporosis in men because it substantially improves bone mass rebuilds the microarchitecture improves bone strength and reduces fractures Little is known about the best ways to employ TPTD in the treatment of male osteoporosis Should it be used only as monotherapy or does concurrent or sequential use with other agents lead to the greatest benefit The proposed clinical trial is an effort to test a novel combination therapy for osteoporosis in men based on exciting preclinical findings in mice It is known that TPTD achieves its anabolic effects by stimulating PTH-Rs in cells of the OB lineage Calcimimetics mimic the effects of high extracellular calcium concentrations Cae by activating CaSRs expressed in many cell types including OBs and OCs in bone
ASpecific Aims and Hypotheses Tested To address the hypothesis that concurrent CaSR and PTH-R activation produces synergistic anabolic effects on bone a double-blind PBO-controlled trial in 48 men with low BMD testing a novel combination regimen will be performed Older male Veterans with low BMD by DXA will be randomized to 2 treatment arms TPTDcinacalcet vs TPTDPBO Efficacy endpoints will be changes in BMD by DXA and the bone turnover marker BTM P1NP Aim 1 Pharmacodynamic PD effects of the combination regimen vs monotherapy will be profiled serum Ca PTH and safety confirmed Aim 2 A subset of 24 patients 12treatment arm will undergo detailed acute 8 hr PD assessments and clinical monitoring at the UCSF CRC Clinical Research Center Safety will be assessed in all trial subjects with serum Ca and 24-hour urinary Ca monitoring and with adverse event AE and clinical assessments Although both drugs used in this trial are FDA-approved TPTD 20 ugday for osteoporosis cinacalcet 30 mgday for HPT an IND Investigational New Drug application is in place to give this drug combination
BStudy Aims and Hypotheses AIM 1 To determine the effects of treatment with TPTDcinacalcet compared to TPTDPBO on BMD and bone metabolism in men with low bone mass by assessing responses in lumbar spine LS BMD primary endpoint and femoral neck FN BMD and levels of P1NP
There are 2 hypotheses tested in this aim Hypothesis 1a proposes that BMD responses to combined TPTDcinacalcet are greater than those induced by TPTDPBO LS BMD typically responds quickly and robustly to TPTD and is the 1o endpoint of the trial Changes in FN BMD a site often slower to respond and with smaller magnitude are a 2o endpoint DXA measurements will be performed and analyzed as described below Subjects will be treated for 11 months 48 weeks All subjects will receive Ca and vitamin D3 supplements throughout the trial Hypothesis 1b proposes that bone formation marker P1NP increases to a greater extent with combined TPTDcinacalcet vs TPTDPBO P1NP is the best validated biomarker of TPTD action and responds rapidly and robustly to anabolic therapy the change in P1NP at 3 months 12 weeks after initiation of treatment is a key 2o endpoint for the study
AIM 2 To determine the pharmacodynamic PD responses to study drug administration in men with low bone mass by assessing acute and chronic changes in the serum Ca and plasma intact PTH after drug administration and changes in urinary Ca excretion
There are 2 hypotheses tested in the PD studies in this aim which is focused on establishing physiologic responses and confirming safety with this combination therapy Hypothesis 2a proposes that the serum Ca does not fall to 5 below the lower limits of the normal range in response to the administration of study drugs After randomization subjects will initiate dosing with the 2 study drugs First baseline sampling pre-study drug will be done and then subjects will have blood collected for serum Ca albumin and PTH at specific time-points in the 8 hours after study drugs are administered As is clear from the literature on PTH actions in vivo TPTD tends to raise serum Ca while cinacalcet is expected to lower intact PTH and thereby serum Ca usually transiently It is anticipated that the effects of these 2 drugs known to act over similar time-courses in humans will tend to offset each other so that the serum Ca remains stable and within the normal range in subjects taking the combination TPTDcinacalcet In general the majority of patients taking TPTD and the majority of those receiving cinacalcet should experience offset of drug effects well before 24 hours have elapsed post-dosing Based on these kinetics it is not expected that combined treatment will produce major steady-state changes in serum Ca At the very least it is expected that any serum Ca lowering will be modest and transient and steady-state levels will not drop 5 below the lower limit of the normal range This will be carefully assessed both acutely in the PD study in 24 subjects 12treatment arm and chronically by examining pre-dose serum Ca over the full study in all subjects Intact PTH will be monitored as an exploratory endpoint since serum PTH levels may fall with chronic cinacalcet treatment Determining changes in endogenous PTH secretion may be important for fully understanding the PD of concurrent TPTDcinacalcet therapy
Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg24 hours in subjects receiving study drugs This parameter will be carefully studied throughout the trial for these reasons First TPTD may raise urinary Ca because of increased gut Ca absorption due to increased 125OH2 vitamin D and enhanced Ca mobilization from bone direct PTH action Both effects increase the filtered load of Ca which can raise urinary Ca Second calcimimetics by stimulating renal CaSRs may also raise urinary Ca levels Hypothesis 2b is predicated on the observation that men treated with TPTD alone did not excrete 350 mg Ca24 hours according to prior clinical trial data In addition prior studies in patients with 1o HPT did not show significant hypercalciuria due to cinacalcet However data on urinary Ca in normal subjects taking calcimimetics are scant If chronic hypercalciuria results from the combination therapy there is potential for consequences renal stones possibly renal insufficiency that will be key to know about Thus urinary Ca assessments throughout the study are critical safety endpoints
CPrimary and Secondary Objectives As primary objective the study will examine the effects on LS BMD by DXA of treatment with the combination of TPTD PTH 1-34 placebo vs TPTD oral calcimimetic cinacalcet in men with low bone mass or osteoporosis
The study has two secondary objectives 1 assess the effects of combination of TPTD PTH 1-34 placebo vs TPTD oral calcimimetic cinacalcet on FN BMD by DXA in men with low bone mass or osteoporosis and 2 assess the effects of the combination of TPTD PTH 1-34 PBO vs TPTD oral calcimimetic cinacalcet on the bone formation marker serum P1NP in men with low bone mass or osteoporosis
A safety assessment will include determining a acute and chronic changes in the concentrations of serum Ca Ca and plasma intact PTH after administration of study medications in both treatment arms in an 8 hour PD study and b changes in 24 hour urinary Ca excretion over full 11 month trial with both treatment regimens
4 Study Design and Protocol
ASubjects There will be 48 men randomized to one of two treatment arms TPTD PBO tablet N24 or TPTD cinacalcet tablet N24 Men of all ethnic and racial groups will be encouraged to participate The DXA scan done at screening will be used to determine whether or not a man meets BMD criteria for enrollment into the study
BInclusion and Exclusion Criteria for Subjects - described elsewhere in the application
CStudy Drugs and Supplements Teriparatide TPTD or PTH 1-34 which will be obtained from commercial sources and given at 20 mcg daily by SC injection Cinacalcet or sensipar an oral calcimimetic will be given at the dose 30 mg daily orally
The PBO control will be a purchased placebo tablet that will be packaged in exactly the same manner as cinacalcet Supplements in the form of Ca citrate tablets 200 or 500 mg tablets will be given in both treatment arms to subjects along with vitamin D3 1000 International Units by mouth daily Ca supplements will be adjusted along with an assessment of dietary Ca intake to reach a total of 1000 mg elemental Ca per day
DStudy Measurements Several types of measurements will be made in the course of the trial
1 BMD will be measured at the LS hip and radius by DXA at the UCSF CTSI CRC Trabecular bone score TBS will also be determined from the data collected during the DXA assessment of the lumbar spine using commercially available software applications available at the investigators center
2 Biochemical markers of bone turnover BTMs and vitamin D metabolites will be measured during the study visits including the following serum P1NP serum C-telopeptide CTX bone specific alkaline phosphatase BSAP osteoprotegerin OPG RANK-L and 125 OH2 vitamin D
3 Dietary Ca intake will be assessed by the Block Food Frequency Questionnaire
4 There will be PD testing during the study This will include assessing acute changes in the serum levels of Ca albumin phosphate and PTH during the acute administration of the study drugs during an 8-hour PD test in the clinic at the Randomization Visit of the study determining chronic changes in the serum levels of calcium and PTH during the entire study with the administration of the study drug combinations 11 months of the trial studying chronic changes in the urinary calcium at study visits during the full trial
5 In exploratory studies peripheral blood mononuclear cells PBMCs will be collected by blood sampling of participants and those samples fractionated for cells of the OB and OC lineage to determine whether the two treatment interventions alter the levels and properties gene expression markers of the circulating populations of these cells
EStudy Duration and Study Visits Subjects will be on study for approximately 12-13 months Screening will be conducted at 2 separate visits This will be followed by a run-in period of 4 weeks for eligible subjects The intervention period will be 11 months 48 weeks in duration
Screening will be done through a telephone call to initiate contact describe the study and set up a visit to achieve informed consent and to do the screening DXA scan There are two Screening Visits the first will involve obtaining the DXA scan and the second will involve lab testing a complete medical history and physical exam to be performed The run-in period during which the participant takes only calcium and vitamin D supplements for 4 weeks will follow
The Randomization Visit will involve lab testing and in 1224 subjects in each arm an 8-hour PD Study Subjects will be randomized to one of the study treatment arms and taught to take the daily injections and the study medication tablets cinacalcet vs PBO At week 1 subjects will have lab testing done and a telephone visit Thereafter at Weeks 4 8 12 20 24 36 and 48 there will be lab testing of blood and urine assessment of adverse events and clinical followup done At the final visit Week 48 approximately 11 months a followup DXA scan will be done
FTimeline of main study procedures and interventions Momonth
Screening Visit 1
-Informed consent DXATBS
Screening Visit 2
-History physical exam vital signs screening labs blood urine food frequency questionnaire AE concomitant medications pen teaching supplements dispensed
Randomization Visit -PD study vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 1 Visit
-Lab tests AE concomitant medications Cavitamin D intake check
Week 4 1 Mo Visit -Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 8 2 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 12 3 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 20 5 Mo Visit -Vital signs labs blood AE concomitant medications pen teaching supplements and study drugs dispensed extra blood collected Cavitamin D intake check
Week 24 6 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 36 9 Mo Visit
-Vital signs labs blood urine AE concomitant medications pen teaching supplements and study drugs dispensed extra blood and PBMCs collected Cavitamin D intake check
Week 48 11 Mo Visit
-DXA TBS history physical exam vital signs labs blood urine AE concomitant medications extra blood and PBMCs collected Cavitamin D intake check
5Study Analysis
Statistical Analysis Plan
Statistics will include descriptive as well as analytic approaches The intention-to-treat ITT approach will be used with all randomized men included in the analysis Complete follow-up data will be collected on every randomized subject regardless of adherence 2o per-protocol analyses will be done limited to those who remained on medication and those with complete data All statistical testing will be performed at nominal 005 level without adjustments for multiple comparisons
Analysis of Primary Endpoint
To determine the effects of 11 months of treatment with TPTDcinacalcet compared to TPTDPBO on LS BMD primary endpoint Testing the 1o hypothesis for the effect of the 2 treatment arms on the change in LS BMD will use a t-test with a two-sided significance level of 005 The extent of missing data will be reported in all statistical analyses Overall missing data rates are expected to be low since the investigators will make every attempt to obtain BMDs at 11 months for all men regardless of medication use 1o analyses will be unadjusted Using standard statistical methods and means and SDs from published TPTD studies the effect size true difference in means between treatment groups that can be detected based on a t-test comparison between treatment groups of the change in LS BMD with a fixed sample size of 24group was calculated Even if 20 of the subjects were lost to follow-up and did not contribute 11-month LS BMD data with a sample size of 40 the study is powered to detect a between-group difference as small as 40 A difference between treatment regimens of 4 eg mean LS BMD increase in TPTDPBO of 5 vs 9 increase in the combination group would be an effect size for BMD in the range that would be clinically promising and support pursuing further studies of this combination therapy for osteoporosis
Analysis of Secondary Endpoints
To determine the effects of 11 months of treatment with TPTDcinacalcet compared to TPTDPBO on FN BMD and levels of the bone formation marker P1NP secondary endpoints
A similar approach will be taken for FN BMD and for the logarithm of the P1NP change as will be taken for the primary endpoint above On an exploratory basis changes in TBS from baseline to study end will be analyzed as BMD is All hypotheses will be tested at the nominal 005 2-sided significance level with no formal adjustment for multiple comparisons In the analysis of 2o outcomes and in other 2o analyses it is recognized that this might increase type 1 error rates due to multiple testing To alleviate that concern 1o and 2o endpoints will be clearly distinguished as well as exploratory analyses Consistency among multiple endpoints will be looked and caution will be exercise in interpreting marginally significant findings particularly unexpected results not motivated by a priori hypotheses The extent of missing data will be reported in all statistical analyses Overall missing data rates are expected to be low since every attempt will be made to obtain BMDs at 11 months and P1NP at 3 months for all men regardless of medication use 1o analyses will be unadjusted
This study has 80 power with an alpha005 to detect a between-group difference in change in FN BMD as small as 35 Since effects of TPTD on FN BMD in short-term studies are small it is recognized that 35 may be an ambitious difference between treatments for hip BMD However the point estimates may give an indication of whether the combination has superior effects on BMD at the hip and help investigators to plan future studies of this combination
The distribution of P1NP change is non-Gaussian in multiple studies requiring log transformation log ratio and back-transformation for presentation Using data from the PaTH Parathyroid Hormone and Alendronate for Osteoporosis trial of the 3-month change in P1NP the back-transformed mean change 95 CI was 148 117 183 Based on the SD of the log ratio in PaTH a sample size of 40 20group assuming 20 non-completers will provide 80 power with alpha005 to detect a difference of 137 eg an increase from 148 to 285 between P1NP responses of men treated with TPTDcinacalcet vs TPTDPBO
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
True
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
True
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 1 IO1 CX001514-01A2 | OTHER_GRANT | Department of Veterans Affairs | None |