Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT03994172 |
| Other study ID # |
ENDB-012-17F |
| Secondary ID |
1 IO1 CX001514-0 |
| Status |
Recruiting |
| Phase |
Phase 4
|
| First received |
|
| Last updated |
|
| Start date |
July 1, 2019 |
| Est. completion date |
June 30, 2025 |
Study information
| Verified date |
July 2023 |
| Source |
VA Office of Research and Development |
| Contact |
Dolores M Shoback, MD |
| Phone |
(415) 221-4810 |
| Email |
dolores.shoback[@]va.gov |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial 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.
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
1.5 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 ~37.5% 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 and/or 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 ug/day; N=10) or PBO (N=13) for 18 months. Finkelstein and colleagues, as part of
a combination study, randomized 27 men to synthetic PTH (1-34) for 24 months (37
ug/day). Thus, that study used twice the approved dose of PTH (1-34). Walker and
colleagues randomized men to risedronate (35 mg/week) (N=10), TPTD (20 ug/day) (N=9), or
the combination (N=10) 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
(1-34)/day]. Higher doses of PTH (1-34) (37 or 40 ug/day) 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 ug/d) 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 PTH(1-34) 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] ([Ca]e), 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 PTH(1-34) (40-80 ug/kg) and the
calcimimetic NPS-R568 (20 umole/kg) 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 volume/tissue volume (BV/TV)] by micro-CT in the
distal femur as well as Tb thickness (TbTh) (p<0.05). Co-injections of PTH (1-34) and
NPS-R568 produced significantly greater effects on Tb BV/TV and TbTh (by ~21%; p<0.01),
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% (p<0.05). 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 BV/TV, TbTh, and Tb number (N); p<0.05 or p<0.01] and in their Ct bone at
the TFJ (CtTV, CtBV, and CtTh; p<0.05) 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 (N=12 mice/group) 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 PTH/NPS-R568
vs PTH (1-34)+vehicle.
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 PTH(1-34)], 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 ([Ca]e) by
activating CaSRs expressed in many cell types including OBs and OCs in bone.
A.Specific 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: TPTD+cinacalcet vs TPTD+PBO. 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 (12/treatment 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 ug/day for osteoporosis; cinacalcet, 30
mg/day for HPT), an IND (Investigational New Drug) application is in place to give this
drug combination.
B.Study Aims and Hypotheses AIM 1: To determine the effects of treatment with
TPTD+cinacalcet compared to TPTD+PBO 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 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. 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 TPTD+cinacalcet vs TPTD+PBO. 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
(TPTD+cinacalcet). 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 (12/treatment
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 TPTD+cinacalcet
therapy.
Hypothesis 2b proposes that urinary Ca excretion does not exceed 350 mg/24 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 1,25(OH)2 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 Ca/24 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.
C.Primary 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
A.Subjects There will be 48 men randomized to one of two treatment arms: TPTD + PBO tablet
(N=24) or TPTD + cinacalcet tablet (N=24). 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.
B.Inclusion and Exclusion Criteria for Subjects - described elsewhere in the application
C.Study 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 (1,000
International Units) by mouth daily. Ca supplements will be adjusted along with an assessment
of dietary Ca intake to reach a total of ~1,000 mg elemental Ca per day.
D.Study 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 1,25 (OH)2
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.
E.Study 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 12/24 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.
F.Timeline of main study procedures and interventions (Mo=month)
Screening Visit 1
-Informed consent, DXA/TBS
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, Ca/vitamin D intake check
Week 1 Visit
-Lab tests, AE, concomitant medications, Ca/vitamin 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,
Ca/vitamin 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, Ca/vitamin 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, Ca/vitamin 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, Ca/vitamin 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, Ca/vitamin 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, Ca/vitamin 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, Ca/vitamin D intake check
5.Study 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 0.05 level without
adjustments for multiple comparisons.
Analysis of Primary Endpoint
To determine the effects of 11 months of treatment with TPTD+cinacalcet compared to TPTD+PBO
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 0.05. 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
24/group 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 4.0%. A difference between treatment regimens of ~4%
(e.g., mean LS BMD increase in TPTD+PBO 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 TPTD+cinacalcet compared to TPTD+PBO
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 0.05 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 alpha=0.05) to detect a between-group difference in change
in FN BMD as small as 3.5%. Since effects of TPTD on FN BMD in short-term studies are small,
it is recognized that +3.5% 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 (20/group, assuming 20% non-completers) will provide 80%
power with alpha=0.05 to detect a difference of +137% (e.g., an increase from 148% to 285%)
between P1NP responses of men treated with TPTD+cinacalcet vs TPTD+PBO.
