Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes Treated With Pyridoxamine
Phase: NA
Conditions: Diabetes Mellitus, Type 2
Sponsor: Columbia University

Advanced Glycation Endproducts and Bone Material Strength In T2D Treated With Pyridoxamine 
AAAR5451 
October 10, 2018 

 
 
  
Is the purpose of this submission to obtain a "Not Human Subjects Research" determination?
No
 
 
Enrollment status:
Open to enrollment or ongoing review of records/specimens
Provide any additional information necessary to explain the study status:
Protocol renewal
Since the last renewal:
Have there been any changes in the relevant literature that would affect the study design or procedures?
No
Have there been any interim findings associated with this study?
No
Have there been any publications resulting from this study?
No
Have any participants been enrolled using the Short Form process?
No
Is there a Data Monitoring Committee (DMC), Data Safety Monitoring Board (DSMB), or other monitoring entity
for this study?
Yes
Is the most recent report attached as part of this submission?
No
Provide an explanation of why the report is not attached and either the attachment date of the most
recently submitted report or when the next report will be available.
The meeting will take place on October 11th, 2018.
Is an annual Progress Report required by the funding organization or coordinating center for this study?
No
Does this submission include a modification?
Yes
Provide a description of, and explanation for, all changes being proposed in this submission:
please find attached the tracked changes on ICF  and protocol.  On the other hand, you may also find the
attachment of table 1 where changes were also made. 
Columbia University Human Subjects Protocol Data Sheet
General Information
Protocol:
AAAR5451(M00Y02)
Protocol Status:
Approved
Effective Date:
10/10/2018
Expiration Date:
10/02/2019
Originating Department Code:
MED Endocrinology (751850X)
Principal Investigator:
Rubin, Mishaela (mrr6)
From what Columbia campus does this research
originate:
Medical Center
Title:
Advanced Glycation Endproducts and bone material strength in T2D treated with
pyridoxamine
Protocol Version #:
1
Abbreviated Title:
B6 for Diabetic Bone
Was this protocol previously assigned a number by an IRB:
No
Renewal Information
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Indicate which sections of the Rascal submission are affected by the proposed modification. Each marked
section must be revised as part of this submission:
Has the consent form been revised in this submission?
Yes
Does this submission include a report of a protocol violation?
No
 
 
Special review type: Check all that apply or check "None of the Above" box.
[  ]Review for 45 CFR 46.118 Determination (involvement of human subjects is anticipated but is not yet defined)
[  ]Funding review for Administrative IRB approval (such as for Center or Training Grants)
[x]None of the above
  
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oversight for this study?
Yes
Select the most appropriate response:
Columbia will be the IRB of record for the study procedures conducted by Columbia researchers (Note: this
response will apply to most submissions).
  
Is this research part of a multicenter study?
No
  
Please indicate if any of the following University resources are utilized:
[  ]  Cancer Center Clinical Protocol Data Management Compliance Core (CPDM)
[  ]  CTSA-Irving Institute Clinical Research Resource (CRR)
[  ]  CTSA- Irving Institute Columbia Community Partnership for Health (CCPH)
[x]  None of the above
 
 
Abbreviated Submission:
The IRB has an abbreviated submission process for multicenter studies supported by industry or NIH
cooperative groups (e.g., ACTG, HVTN, NCI oncology group studies, etc.), and other studies that have a complete
stand-alone protocol. The process requires completion of all Rascal fields that provide information regarding
local implementation of the study. However, entering study information into all of the relevant Rascal fields is not
[  ]General Information
[  ]Exempt and Expedited
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Background
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required, as the Columbia IRBs will rely on the attached stand-alone (e.g., sponsor's) protocol for review of the
overall objectives.
If you select the Abbreviated Submission checkbox and a section is not covered by the attached stand-alone
protocol, you will need to go back and provide this information in your submission. 
  
Study Purpose and Rationale:
Provide pertinent background description with references that are related to the need to conduct this study. If
this is a clinical trial, the background should include both preclinical and clinical data. Be brief and to the point.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 At least 25% of Americans over the age of 65 have type 2 diabetes (T2D), which, in addition to its well-recognized
complications, is accompanied by a high fracture risk, particularly in elderly patients. Importantly, these fractures are
associated with worse outcomes than fractures in the general population. Standard explanations, namely low bone mass
and high bone turnover, do not explain how T2D adversely impacts the aging skeleton. Rather, low bone turnover,
specifically reduced formation of new bone, likely predisposes to a high fracture risk. This is compounded by altered
material properties of bone that together diminish bone strength and increase its propensity to fracture. Both etiologies –
reduced bone formation and altered bone material properties – are increasingly thought to arise from the accumulation of
advanced glycation endproducts (AGEs). Hence, preventing the accumulation of AGEs in bone tissue in T2D patients is a
potential therapeutic strategy with likely effects in reversing bone fragility in T2D.      In fact, there is currently no
therapeutic agent that addresses the specific skeletal abnormalities in T2D. And, while anti-resorptive agents, such as
bisphosphonates, have been utilized widely, there is no prospective clinical trial data for fracture efficacy. Furthermore,
these latter drugs suppress bone turnover, and would seem contrary to the requirement for increased bone formation.
There is thus a critical need for an effective therapeutic intervention that could lengthen the healthy, active years of life in
older T2D individuals. One novel intervention directed to the etiologic culprit, AGE, is pyridoxamine, a naturally occurring
and structurally distinct metabolite of vitamin B6 pyridoxal phosphate. Preclinical data show that pyridoxamine has
specific molecular features which provide a unique multi-pronged effect to inhibit glycation reactions and the formation of
AGEs. Pyridoxamine is also a potent inhibitor of AGE accumulation and improves bone material properties in diabetic
animals. Notably, while it also reduces AGEs in patients with T2D with nephropathy, there are no clinical data on possible
 skeletal benefits in T2D.      Our overarching goal is to reduce fracture risk in older patients with T2D. The specific
objective of this application is to determine whether, in a short intervention study, pyridoxamine reverses bone fragility in
patients with T2D, and to use this pilot data set as a foundation for larger and longer fracture studies. Our preliminary
data show strong correlations between AGE accumulation and both bone formation and bone material properties (Furst 
et al. JCEM, 2016: PMCID: 4891790).  Namely, we have shown that skin autofluorescence (SAF), a marker for tissue
AGE accumulation, correlates strongly with decreased bone formation. Likewise, using a novel impact microindentation
device that provides an in vivo index of cortical bone material properties, namely bone material strength index (BMSi), we
show that older T2D women have increased AGE accumulation and decreased BMSi. Furthermore, T2D women with the
lowest pyridoxamine stores had the highest SAFs and lowest bone formation and BMSi. Together, these data underscore
our central hypothesis: that pyridoxamine treatment in older T2D patients will increase bone formation and bone
material strength by inhibiting AGE accumulation.  If the resulting findings of pyridoxamine’s skeletal benefits in
T2D are translated clinically, a novel and much-needed therapeutic approach is likely to emerge that should
reduce fractures in aging T2D patients.       Towards examining the effect of pyridoximine on bone formation and
material properties, we will conduct a randomized, double-bind clinical study, comprising two specific aims.  In Specific
Aim 1, we will study the effect of pyridoxamine on the formation of new bone in older T2D patients.  For this, we will treat
52 women over 65 years of age with T2D with pyridoximine or placebo, and measure bone turnover markers, namely
P1NP (bone formation) and TRAP-5b (bone resorption), and skin autofluorescence (SAF), a marker for AGE
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accumulation through 5 visits over 1 year.  In Specific Aim 2, we will study the effect of pyridoxamine on bone material
strength in the same cohort of older T2D patients.  For this, we will perform impact microindentation to calculate BMSi at
baseline and year 1.        We expect that the proposed studies will identify positive effects of pyridoxamine on bone
formation and bone material strength in older T2D patients and that the data will support an AGE-mediated mechanism
for bone fragility in T2D. The findings will also define a new role for over-the-counter vitamin B6 in skeletal homeostasis. If
it is confirmed that pyridoxine does improve bone formation and/or bone material properties, this data set will form the
framework for large scale testing to advance the development of pyridoxamine as a therapeutic agent specifically for
diabetic bone fragility. In this way, this project could have a positive impact on the large and ever growing population of
elderly type 2 diabetic patients.   
BACKGROUND, SIGNIFICANCE AND INNOVATION      Data from two well-conducted meta-analyses involving 1.3
million individuals show that aging patients with T2D have a 40-50% increase in the risk of hip fracture. In the general
population, 20% of hip fracture patients die within one year and more than half never regain functional independence.
Post-fracture complications are also worse in T2D. Notably, a cohort study with >1 million patients found an increased
complication risk in hip fracture patients with T2D, with a 27% increase in mortality (95% CI 1.02–1.60). Thus, it is our
premise that healthy active years of life can be extended by reducing fracture risk in T2D.      Studies with extended
follow-up and rigorous fracture adjudication show that skeletal fragility in diabetes occurs despite normal areal
bone mineral density (aBMD) and high body mass index (BMI), and is not explained by increased falls. In contrast
to the increased levels of bone turnover markers noted in postmenopausal osteoporosis, we and others find reduced
bone turnover in T2D.  That fracture risk is increased in T2D, despite increased bone mass and low bone turnover,
implicates other etiologies, such as abnormal bone material properties and/or bone microarchitecture.  Although
increased cortical porosity has been reported using high resolution peripheral quantitative computed tomography, we do
not find evidence of this deficit. Likewise, a large (n=1057) bone microarchitecture study has failed to document increased
cortical porosity in T2D. Nonetheless, a rigorously designed study by Farr et al. of T2D postmenopausal women using
impact microindentation (IMI) has provided evidence for compromised bone matrix properties, measured as bone material
strength index (BMSi). Although most IMI studies are limited by cross-sectional designs, they show that BMSi
discriminates between those with or without osteoporosis-related fractures, and importantly, independent of a BMD. As
noted below, we posit that increased advanced glycation endproducts (AGEs) contribute, at least in part, to the noted
decreases in BMSi, and that skin AGE levels serve as a valid surrogate for bone AGE accumulation. We have therefore
extended the work of Farr et al. to show that longer duration of T2D and higher skin AGEs are associated with reduced
bone material strength and bone formation (Furst et al. JCEM, 2016: PMCID: 4891790). We hypothesize that reducing
AGEs will improve bone formation and bone material strength in older T2D patients and, in doing so, reduce
fracture risk.   Free-floating sugars in prolonged hyperglycemia interact with exposed amino acid residues on collagen
resulting in a reversible Amadori intermediate that undergoes oxidation to form irreversible AGEs. Excess AGEs
compromise bone formation by interfering with osteoblast precursor proliferation and differentiation, cell attachment to the
collagen matrix, and collagen and mineral deposition. Low bone formation, in turn, further increases AGEs, perpetuating a
vicious cycle. Our data confirm that bone formation is reduced in T2D. Notably, histomorphometric indices of bone
formation, namely bone formation rate and osteoblast numbers, as well as serum levels of the bone formation marker
procollagen type 1 amino-terminal propeptide (P1NP) are lower in postmenopausal T2D women (Manavalan et al. JCEM,
 2012; PMCID: 3431571). Bone resorption, likely due to coupling with formation, is also reduced. Relevant to our
hypothesis, there is a strong correlation (r=-0.63, P=0.01) between reduced bone formation (low P1NP) and increased
skin AGEs (skin autofluorescence, SAF) in T2D, whereas no associations are seen in controls.
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      To study whether lowering AGE accumulation in bone will improve bone formation and reduce bone fragility in T2D,
we propose to utilize a metabolite of vitamin B6, pyridoxamine. Prospective cohort studies, albeit limited in scope, support
this notion. The Rotterdam Study showed that lower B6 intakes were associated with a higher fracture risk25. Likewise,
the Framingham Osteoporosis Study reported that lower B6 levels were associated with higher bone loss and hip
fractures. In preclinical studies, pyridoxamine is a potent AGE inhibitor possessing specific molecular features that are not
present in other B6 isoforms (pyridoxal and pyridoxol). Based on a pyridine ring structure, with OH, CH3, NH2 and CH2OH
 substituents, pyridoxamine is unique in inhibiting AGE formation (Fig. 1). Voziyan and others showed that the OH at
position 3 and NH2 group at position 4 of its ring endow pyridoxamine with a unique triple mechanism of action: (i)
inhibition of AGE formation by binding of catalytic redox metal ions, thus blocking oxidative degradation of the Amadori
intermediate of the Maillard reaction; (ii) direct scavenging of toxic carbonyl products of glucose and lipid degradation;
and (iii) trapping of reactive oxygen species. While rodent models show that pyridoxamine inhibits AGE-mediated
diabetes complications, including diabetic nephropathy and retinopathy, clinical data are scant. In a phase II study in
patients with diabetic nephropathy, pyridoxamine reduced plasma AGE levels over 6 months, suggesting not only the
inhibition of new AGE formation but also removal of existing AGEs. Albeit limited by a post hoc analysis, serum creatinine
levels also decreased by ~48% (P =0.03). A prospective randomized study of pyridoxamine for 1 year in proteinuric T2D
nephropathy patients showed that only those with less advanced disease responded to pyridoxamine. Of note, plasma 
pyridoxamine is only detectable in subjects given pyridoxamine, but not in untreated subjects whose plasma levels are
below the detection limit. As pyridoxamine easily reacts with carbonyls in the circulation and is converted into pyridoxal,
the latter is the dominant measurable form of vitamin B6 in plasma. We have therefore used serum pyridoxal levels as a
surrogate for circulating pyridoxamine, and find, in 6 patients with T2D, a strong correlation between serum pyridoxal and
the bone formation marker P1NP (r=0.79, P=0.06). These data further support our working hypothesis that
pyridoxamine increases bone formation in older T2D patients by preventing new AGE formation
(Fig. 2).
      In addition to a direct action on osteoblastic bone formation, AGEs impair bone biomaterial properties with an
eventual negative effect on bone strength. The sharp increase in bone pentosidine, a key AGE, in insulin-deficient
diabetic rats is associated with a lower femoral bending stiffness versus wild type littermates, despite no differences in
BMD. Likewise, in our mouse model of type 1 diabetes (T1D), the increase in bone AGE content was correlated inversely
with bone toughness (Rubin et al. PLoS One, 2016; PMCID: 4854398). A relationship between AGEs and bone strength
has also been established in a small clinical study in which trabecular bone from fracturing T1D patients exhibited higher
pentosidine levels than non-fracturing T1D or controls. These correlations have not been observed in T2D, apart from our
preliminary studies. Notably, in older patients with T2D, we find a strong inverse correlation between AGEs and BMSi (r=-
0.65, P=0.006). Thus, we hypothesize that the inhibition of new AGE formation by pyridoxamine will improve
bone material properties and reduce fracture risk in older diabetic patients. Our preliminary data in 6 older T2D
women show that serum pyridoxal (pyridoxamine) levels tend to be lower in patients with the lowest BMSis (r=0.71, P
Fig. 1. Pyridoxamine. The functional
groups inhibit AGE accumulation.
Fig. 2. Hypothesis of Pyridoxamine Effect on Bone in Older
T2D Patients. Inhibition of AGEs will lead to improved bone
formation (SA1) and/or bone material strength (SA2).
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=0.1) and highest skin AGEs (r =-0.67, P=0.1). Together, these data suggest that pyridoxamine correlates with bone
material properties in diabetes, specifically via AGE accumulation.
  
Study Design:
Describe the methodology that will be used in this study, covering such factors as retrospective vs. prospective
data collection, interventional vs. non-interventional, randomized vs. non-randomized, observational,
experimental, ethnography, etc.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 In a small cohort of 6 patients with T2D, we find a strong correlation between serum pyridoxal levels (a
surrogate for pyridoxamine) and the bone formation marker P1NP (r=0.79, P=0.06).  We will therefore test
the working hypothesis that pyridoxamine increases bone formation by preventing new glycation of
collagen.  For this, we will use an interventional protocol to determine whether pyridoxamine alters bone
formation in older T2D patients.  Our overall approach will be to compare the change in bone formation in
response to pyridoxamine vs. placebo given for 12 months.  We expect that pyridoxamine will increase
serum P1NP levels in older T2D.  Furthermore, we expect that those with milder T2D and lower AGEs will
display a greater response magnitude.  These results should provide preliminary data for future studies on
the potential use of pyridoxamine as a specific therapeutic for diabetic bone fragility.Study Protocol: We will
compare the effect of pyridoxamine dihydrochloride (200 mg po bid) (n=26) vs. identical placebo (n=26) in a 1
year double-blind randomized study of older postmenopausal T2D. This dose is available over-the-counter and is
safe and effective at lowering serum AGEs in T2D patients. Study drug (HPLC-certified content, see Appendix)
and placebo will be supplied by LifeLink Pharmaceuticals. A neurological safety evaluation will be performed per
 visit for the unlikely onset of vitamin B6 neurotoxicity (see Human Subjects). Our Research Pharmacy will
randomize patients with a block scheme stratifying for race. We will not stratify for baseline vitamin B6 levels
because they are not expected to modify the response to pyridoxamine,. In addition to evaluating P1NP, serum 
tartrate-resistant acid phosphatase 5b (TRAP-5b) levels will be measured as a surrogate for bone resorption.
AGE levels will be determined using our skin autofluorescence (SAF) protocol, with authentication in a sub-set
(n=10) by bone biopsy AGE measurements.Patient Recruitment: Participants will be recruited from Medicine and
Endocrinology clinics at Columbia, where >1,000 T2D outpatients are seen annually with 60% of local residents carrying
a diagnosis of T2D. We will also recruit from 2 satellite locations in Washington Heights and Riverdale, where >2,400 T2D
patients are seen annually. We have used these populations to recruit >100 T2D in prior studies (Furst et al. JCEM, 2016:
PMCID: 4891790). Dr. Starr (Co-I) will support recruitment.  Her clinic sees ~15 postmenopausal T2D patients every
week; these patients are mostly hospital employees and interested in research participation.  Based on these resources,
we do not foresee any difficulty in recruiting 52 patients within 6 months.  d.   Inclusion and Exclusion Criteria: We will
include postmenopausal women (n=52) 65 years with T2D who meet ADA criteria (HbA1c 6.5%). African Americans, in
whom T2D is common, will be included (n=4/group). In addition to exclusions noted in Table 1 (which can be seen
attached), certain specific considerations apply.  First, and importantly, we will not screen for serum pyridoxamine as 
levels are very low (~10 nM) in those not on pyridoxamine supplementation and are thus unlikely to predict response to
therapy.  Of note is that, with supplementation, levels increase to ~10 µm. It is also unknown whether circulating
pyridoxamine is reflective of bone levels. Second, we will not exclude patients based on serum pyridoxal values.  While
we have used these as a surrogate for pyridoxamine in our preliminary studies, they do not fully capture pyridoxamine
because pyridoxal is also derived from pyridoxine.  Third, low vitamin D (serum 25OHD <30 ng/dl) can be exclusionary as
it is often low in T2D and can be a confounder. Although the IOM threshold is <20 ng/dl, our higher cut-off will avoid any
possibility of deficiency.  However, if the subject's vitamin D level results are less than 20ng/ml and they meet all other
criteria, the investigator will prescribe 50,000 IU of vitamin D weekly for one month and then the subject will be re-
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screened.  Fourth, the blood thinners Clopidogrel, and Rivaroxaban will not be exclusionary because there has been no
excessive bleeding with the use of these agents with microindentation according to Dr. Adolfo Diez-Perez, a leader in the
technique of microindentation.  Finally, insulin users will not be excluded because even though insulin has been
implicated in increasing fracture risk, it is probably not due to insulin itself, but rather due to the disease or comorbidities.
Potential Sources of Biological Variation: We will control for known age-associated bone changes (see Statistical
Analysis). We will also restrict our study to postmenopausal women in view of our preliminary data, and because
including men in a relatively small cohort will only increase heterogeneity.  Moreover, postmenopausal women are at
higher fracture risk and thus might be more likely to display a pyridoxamine treatment benefit on fractures numerically
even in a small cohort.  We will include T2D men in an extended cohort in a future R01 application.  Little is known about
the influence of race on the mechanisms of diabetic bone fragility. We will thus assess our outcomes separately and in
combination with race to assess group differences (see Statistical Analysis). Variables related to fracture risk, such as
nephropathy; years since menopause; nutrient intake; weight; weight bearing exercise; and sun exposure will be treated
as confounders.Patient Visits: At the screening visit, we will assess demographics and covariates using a 
questionnaire [footnote[1]]. We will obtain an AM fasting metabolic panel (BMP) with liver function, HbA1c and 25-
hydroxyvitamin D. BMP and HbA1c are measured by colorimetric assays (Cobas Integra 400 Plus); 25-hydroxyvitamin D
is measured by LCMS on an Agilent 6430 (intra- and inter-assay variability <10%). Patients meeting criteria will undergo
randomization, where we will measure bone mineral density (BMD) by a dual energy X-ray absorptiometer (DXA) using
standard protocols within a month of the screening visit (Table 2).
     At each subsequent study visit as seen in (Table 2):randomization/baseline (0b), month 1 (M1), month 6 (M6), month
9 (M9) and month 12 (M12), we will measure serum intact P1NP by radioimmunoassay (IDS; intra- and inter-assay
variability <10%). Note that considering that stage I-II CKD may be present, it would be important to measure intact
P1NP, which represents the trimeric form that is not renally cleared. TRAP-5b will be quantified by ELISA (IDS; intra- and
inter-assay variability of 10%). TRAP-5b is selected because it is an enzyme derived from osteoclasts and unlike serum
C-telopeptide (derived from collagen) will not be affected by alterations in collagen degradation due to glycation, the
screening,(0b), M12 visits, we will measure Skin Autofluorescence (SAF), which we and others have shown is highly
reproducible.  Notably, this new technique effectively measures tissue AGE accumulation and has been validated against
direct AGE measurements including pentosidine levels in skin. The PI is experienced in SAF measurements and obtained
relevant preliminary data (Furst et al. JCEM, 2016: PMCID: 4891790). SAF is measured with the AGE Reader
(DiagnOptics Technologies BV).Preliminary Validation of AGE Testing: Extrapolating from skin to bone may be
imprecise, as skin collagen has a longer half-life than bone collagen and glycated skin proteins might be absent in bone. 
 Therefore, prior to randomization, we will perform a preliminary corroboration of our SAF technique with direct
measurement of AGEs in bone biopsies in a randomly selected, albeit small, sub-set of Caucasian patients with high (2.6;
n=5) or low (2.0; n=5) SAF levels. We have not proposed biopsies for all subjects because of invasiveness, time and cost.
The biopsy AGE assay will precisely quantify the degree of collagen glycation with a fluorometric assay that is routinely
used by our collaborator, Dr. Deepak Vashisth (Professor of Biomedical Engineering, RPI; see Letter). Cortical and
cancellous compartments will be analyzed separately because of known compartment differences in glycation.  The PI
has long-standing experience in obtaining biopsies and our collaborator is a leading expert in measurement of bone
glycation.  Power Calculations: Assuming our preliminary findings, mean ± SD P1NP of 51.2 ± 16.2 in healthy
controls and 38.4 ± 9.8 in T2D, a standardized difference of 0.95-SD, and 80% power, a 1%  and an analysis of
covariance (ANCOVA) where covariates have a correlation with outcome of r = 0.50, normalization of P1NP at 1-
year requires 20 subjects in each group49. This allows us to have an adjusted 95% confidence interval surrounding the
between group difference in means of ± 4.99 for a minimum detectable 13% increase in P1NP in the T2D. We propose to
increase enrollment by 6 subjects per group to both enroll minority subjects (n=4/g) and for potential attrition (n=2/g).
Between treatment group differences in minority enrollees will be an exploratory analysis to provide estimates for future
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study design parameters. 
     
  
Statistical Procedures:
Provide sufficient details so that the adequacy of the statistical procedures can be evaluated including power
calculations to justify the number of participants to be enrolled into the study. Definitions of subject terms such
as enrolled and accrued as used for Rascal submissions can be found in the Subjects section.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 Briefly, data will be reviewed for accuracy, completeness and assumptions held for categorical variables and
distributional characteristics of continuous variables. Transformations will be applied prior to inferential testing as
necessary to achieve normal distributions. The pattern of missing data will be examined and, if found to be missing
completely at random or missing at random, the fully conditional specification multiple imputation method of Van Burren50
.  The primary outcome is the 1-year change in the P1NP marker of bone formation and the primary intent-to-treat
analysis is a one-way ANCOVA with fixed effect of treatment (treated vs. placebo), and baseline P1NP as a continuous
covariate. Secondary outcomes of TRAP-5b and SAF will be analyzed in similar ANCOVA models with P-value
adjustment for multiple endpoint comparisons. Exploratory analyses will employ linear mixed models for repeated
measures to estimate the between treatment group difference in the temporal course of change in P1NP, TRAP-5b and
SAF with fixed effect of treatment, time (baseline, 1, 6, 9 and 12-months), random effects for subject and the baseline
value of the outcome, and a covariance structure chosen by empirical fit prior to inferential testing. The influence of
additional theoretical confounders will be explored in this model: age, duration of T2D, diabetes complications and
baseline DXA. Predictors of the change in P1NP in the pyridoxamine-treated group will be estimated using multiple linear
regression to identify variables that track or lead changes in P1NP. Bone collagen glycation differences in the subset of
randomly selected high and low SAF patients at baseline will be assessed by T-test and, although underpowered, an
intraclass correlation coefficient calculated to quantify agreement between bone and skin AGE content. Expected
Outcomes and Data Interpretation: We expect that P1NP levels will increase with pyridoxamine at 1, 6, 9, and 12
months vs. placebo. We anticipate that P1NP will increase to a greater extent in those with milder T2D. This expectation
is based on published pyridoxamine data in T2D nephropathy patients, where those with milder disease responded best
to pyridoxamine33. Our preliminary data that P1NP levels are lowest with the highest AGEs6 leads to a similar
expectation. It is thus anticipated that lower baseline SAF levels (known to be associated with shorter T2D duration, fewer
T2D complications and higher baseline P1NP levels) will predict a greater increase in P1NP with pyridoxamine. Also, as
noted with other agents, such as teriparatide51, serum TRAP-5b levels are also expected to increase because of the
coupling between bone formation and bone resorption.  We do not anticipate baseline BMD to predict change in P1NP,
as it does not relate to bone formation levels or SAF in our preliminary data (Furst et al. JCEM, 2016: PMCID: 4891790)6. 
 A decline in SAF is also expected with pyridoxamine; however, this may not be detectable by 12 months, especially
because skin turnover might underestimate bone turnover. We also expect that SAF levels in the biopsy sub-set of
patients will correlate with direct bone AGE levels, as a preliminary authentication our skin test. Overall, we expect these
outcomes to identify an effect of pyridoxamine to increase bone formation via an AGE-inhibiting mechanism. This sets the
stage for reversing diabetes-specific skeletal deficits, which until now has not been possible with approved osteoporosis
therapies.
1Covariates for Questionnaire: age; race; duration of T2D; co-morbidities including hypertension, nephropathy, neuropathy,
retinopathy; weight; diabetes medication(s); medical history; medications; menopause age; nutrient intake; weight bearing exercise;
and sun exposure.
 
 
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Is the purpose of this submission to obtain an exemption determination, in accordance with 45CFR46.101(b):  
No
  
Is the purpose of this submission to seek expedited review , as per the federal categories referenced in
45CFR46.110?
No
 
 
Is there any external funding or support that is applied for or awarded, or are you the recipient of a gift, for this
project?
Yes
 
 
 
 
Exempt and Expedited
Funding
Award Type
Funding
Source
Name
Name of
awarding
agency
Status
Award # or
Application
Date
Federal/State
/Local
Government
Direct or
Subcontract
What is the
award
covering?
Rascal PT
Number
Federal/State/
Local
Government
NIH
National
Institute on
Aging/NIH/DH
HS
Applied
for/Proposed
02/14/2017
Direct
Recipient: No
Subcontract
Sites
Entire
Protocol
PT-
AABN4168
Locations
Location Type
Facility Name
Domestic or
International
Geographic
Location
Local IRB Ethics
Approval
Local Site
Approval
Offsite
Columbia Doctors
Riverdale 3050
Corlear Avenue,
Suite 204, Bronx,
NY 10463
Domestic
Bronx, NY
Unsure if approval
is needed
Unsure if approval
is needed
Columbia/CUMC
180th Fort
Washington,
Harkness Pavilion,
9th Floor Rm 945,
New York, NY
10032
Personnel
UNI/Phone
Name
Role
Department
Edit/View
Obtaining
Informed Consent
mrr6
Rubin, Mishaela
Principal
MED
Edit
Y
IRB-AAAR5451
Page 9 of 30
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UNI/Phone
Name
Role
Department
Edit/View
Obtaining
Informed Consent
212-305-7859
Investigator
Endocrinology
(751850X)
Roles and Experience:  principal leader of the study including recruitment, eligibility criteria, data
bo2248
212-342-3687
Omeragic, Beatriz
Coordinator
MED
Endocrinology
(751850X)
Edit
Y
gt2397
212-305-6257
Tabacco, Gaia
Other Engaged
Personnel
MED
Endocrinology
(751850X)
Edit
Y
Roles and Experience:  Recruiter
jrf2147
516-242-0170
Starr, Jessica
Investigator
MED
Endocrinology
(751850X)
Edit
Y
Roles and Experience:  help recruit, perform study, analyze data
mps2205
212-304-5536
Siu, Monica
Coordinator
MED
Endocrinology
(751850X)
View
Y
rm3324
212-305-3231
Majeed, Rukshana Coordinator
MED
Endocrinology
(751850X)
Edit
Y
xij2000
646-577-2343
Javier-Espinal,
Xiomara
Coordinator
MED
Endocrinology
(751850X)
Edit
Y
Training and COI
The PI must ensure that each individual that is added as personnel has met the training requirements for this
study (http://www.cumc.columbia.edu/dept/irb/education/index.html). For help identifying which research
compliance trainings you may be required to take, visit the Research Compliance Training Finder.
UNI
Name
COI
HIPAA
HSP
(CITI)
Researc
h with
Minors
(CITI)
FDA-
Regulat
ed
Researc
h (CITI)
S-I
CRC
Good
Clinical
Practice
(GCP)
GCP -
Third-
party
tracking
Genetic
Researc
h
Consent
mrr6
Rubin,
Mishaela
10/09/20
18
07/27/20
14
06/22/20
18
05/21/20
15
05/21/20
15
04/15/20
18
09/29/20
17
bo2248
Omeragi
c,
Beatriz
05/14/20
18
11/06/20
15
09/01/20
16
09/01/20
16
11/10/20
15
11/12/20
15
09/27/20
16
gt2397
Tabacco
, Gaia
11/05/20
17
11/05/20
17
11/10/20
17
11/10/20
17
11/10/20
17
jrf2147
Starr,
Jessica
05/03/20
18
09/26/20
13
09/26/20
16
09/26/20
16
09/26/20
17
mps220
5
Siu,
Monica
08/02/20
18
07/11/20
18
07/19/20
18
07/19/20
18
07/30/20
18
07/26/20
18
rm3324
Majeed,
Rukshan
a
03/15/20
18
04/14/20
15
09/21/20
16
09/21/20
16
09/21/20
16
04/14/20
15
04/14/20
15
09/27/20
16
xij2000
Javier-
Espinal,
Xiomara
06/28/20
18
06/07/20
18
06/29/20
18
06/25/20
18
07/10/20
18
Departmental Approvers
IRB-AAAR5451
Page 10 of 30
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Indicate the methods by which data/research records will be maintained or stored (select all that apply):
[x]Hardcopy (i.e., paper)
Describe where and how the data will be stored:
Study documents will be labeled with a code and locked in the investigator's office. The code to the subjects will be
kept in a separate file cabinet, also locked in a file cabinet in the investigator's office. Only members of the study
team who must access the study data will have access to the files. Study data will also be collected in password
protected computer files that are stored on the Department of Medicine MC Domain Server (IP Address:
10.171.8.150), a multi-user server that has been registered and certified by CUMC IT(System ID number:3924).
The server will be accessed through password protected computers only (no laptops, no portable data drives).
[x]Electronic
Where will the data be stored?
Y
[x]On a System
[  ]On an Endpoint 
Does this study involve the receipt or collection of Sensitive Data?
Yes
If any Sensitive Data is lost or stolen as part of your research protocol, you must inform both the IRB and the
appropriate IT Security Office (CUMC IT Security if at CUMC; CUIT if at any other University campus).
 
What type of Sensitive Data will be obtained or collected? Select all that apply:
[  ]Personally Identifiable Information (PII), including Social Security Numbers (SSN)
Will Social Security Numbers (SSNs) be collected for any purpose?
[x]Protected Health Information (PHI), including a Limited Data Set (LDS) 
If any PHI is lost or stolen, you must inform both the IRB and the Office of HIPAA Compliance.
 
 
Indicate plans for secure storage of electronic sensitive data: check all that apply
[x]Sensitive data will not be stored in electronic format
[  ]Sensitive data will be stored on a multi-user system
[  ]Sensitive data will be stored on an encrypted endpoint
Provide a description of how the confidentiality of study data will be ensured, addressing concerns or
protections that specifically relate to the data storage elements identified above (e.g. hard copy, electronic,
system, and/or endpoint):
Study documents will be labeled with a code and locked in the investigator's office. The code to the subjects will be kept in
a separate file cabinet, also locked in a file cabinet in the investigator's office. Only members of the study team who must
access the study data will have access to the files. Non-sensitive study data will also be collected in password protected
computer files that are stored on the Department of Medicine MC Domain Server (IP Address: 10.171.8.150), a multi-user
server that has been registered and certified by CUMC IT (System ID number:3924). The server will be accessed through
Electronic Signature:  Mishaela Rubin (751850X) - Principal
Investigator
Date:  10/08/2018
Privacy & Data Security
IRB-AAAR5451
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password protected computers only (no laptops, no portable data drives).
 
Is there or will there be a Certificate of Confidentiality (CoC) for this research?
No
Provide a description of the protections in place to safeguard participants' privacy while information is being
collected:
Patients will only be interviewed by Drs. Starr and Rubin in a private room to ensure their PHI is not inappropriately
revealed. Data will be collected and recorded on case report forms on which the only identifier is a research ID code,
which will be a code. Only the PI and project coordinator has access to the link between the research ID code and PHI,
which will be kept in a separate password protected file. No names or identifying information will accompany specimens.
 
 
Is this project a clinical trial?
Yes
Is this project a clinical trial that requires registration with www.clinicaltrials.gov?
No
Is this project associated with, or an extension of, an existing Rascal protocol?
Yes
Existing Rascal protocol #:
AAAE1078
Do study procedures involve any of the following?
Analysis of existing data and/or prospective record review
No
Audio and/or video recording of research subjects
No
Behavioral Intervention?
No
Biological specimens (collection or use of)
Yes
Cancer-related research
No
Drugs or Biologics
Yes
Future use of data and/or specimens
Yes
Genetic research
No
Human embryos or human embryonic stem cells
No
Imaging procedures or radiation
Yes
Medical Devices
Yes
Surgical procedures that would not otherwise be conducted or are beyond standard of care
Procedures
IRB-AAAR5451
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No
Will any of the following qualitative research methods be used?
Survey/interview/questionnaire
Yes
NOTE: You must attach a PDF version of the survey(s)/interview(s)/questionnaire(s) to this protocol prior
to submission.
Systematic observation of public or group behavior
No
Program evaluation
No
Will any of the following tests or evaluations be used?
Cognitive testing
No
Educational testing
No
Non-invasive physical measurements
Yes
Taste testing
No
Is there an external protocol that describes ALL procedures in this study?
No
Please describe ALL study procedures in detail.
NOTE: Be sure to detail all of the procedures above to which a "yes" response was selected. Also detail any
additional procedures that may or may not fall into the categories listed above.
 
1) DXA will be performed twice. This will be done at Baseline visit and M12. This is a testing of bone mineral density.
2) 6 tubes (about ten teaspoons) of fasting blood will be collected during the screening from subjects and controls to
measure:
calcium, glucose, HgbA1c, creatinine, 25hydroxyvitamin D, and bone turnover marker
(TRAP-5b).  At screening visit, baseline, M1, M6, M9, and M12, we will draw 3 tubes of blood (about five teaspoons) to
measure P1NP (a marker of bone formation) and TRAP-5b (a bone turnover marker reflective of osteoclast activity).
3) 1 tube of serum blood samples will be collected from all African American subjects and all controls (random sample)
to measure blood pentosidine levels.
Either during the screening, randomization, or M12 visits, the following will be studied:
4)A measure advanced glycation endproducts (AGEs) in the skin will be made using a noninvasive measurement of
skin autofluorescence (SAF), a method based on the fluorescent properties of AGEs. We will perform this test at,
screening, baseline and at M12.  Participants will be asked not to use any sunscreen within 2 days before the
measurement. All measurements will be performed at room temperature in a semi-dark environment while participants
are at rest in a seated position. The forearm of a participant will be positioned on top of the device. SAF will be
measured with the AGE Reader (DiagnOptics Technologies BV). The AGE Reader is a desktop device that uses the
characteristic fluorescent properties of certain AGEs to estimate the level of AGE accumulation in the skin. The AGE
Reader illuminates approximately 4cm2 of the skin (which is guarded against surrounding light) with an excitation light
source of 300-420nm (peak excitation 350nm). Autofluorescence is then calculated by dividing the average light
intensity emitted per nm over the 420- to 600-nm range by the average light intensity emitted per nm over the 300- to
420-nm range. Control measurements will first be obtained with the lights off, autofluorescence of the skin will then be
measured six times (every 10 seconds) at the volar side of the arm, approximately 10mc below the elbow fold. This
procedure involves no risk to the subject and is completely noninvasive.
5) Transiliac percutaneous bone biopsy will be performed in a total of 10 subjects for assessment of bone structure,
IRB-AAAR5451
Page 13 of 30
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bone metabolism and quantification of advanced glycation end products in collagen. An additional separate consent
form will be used for the bone biopsy. Participants who undergo the bone biopsy will be compensated $250.
6) Reference Point Indentation via a microindentation at the midshaft of the anterior tibia will be performed for
assessment of bone material strength (BMS) in a minimally invasive approach that uses a hand-held probe
(OsteoProbe®) to obtain indentation measurements of bone. We will perform this procedure at baseline and at M12.
The procedure will be performed in an exam room under sterile conditions. 2% lidocaine will be used as a local
anesthetic. The lidocaine will be administered by 2 study physicians, Drs. Mishaela Rubin and Jessica Starr who are
also going to be the only two study physicians doing the microindentation procedure. Both Drs. Starr and Rubin have
learned how to use lidocaine injections as part of their general medical training (medical school and internal medicine
residency). Additionally, Dr. Starr, one of the study physicians, met with Dr. Adolfo Diez-Perez, the investigator who
has pioneered the technique and has performed microindentation in hundreds of subjects. He reviewed the procedure
in detail with Dr. Starr and she observed the actual procedures with him. Secondly, we have both successfully used
the tool in research protocol AAAE1078. The probe will be held perpendicular to the tibia as the leg is flat against the
exam table and will be inserted through the soft tissue and periosteum until it reaches the bone surface. The
indentation occurs via trigger mechanism and takes 0.25ms. The size of the indentation is quite small, about 187m,
which is approximately the width of 1-2 human hairs. The measurement obtained from this procedure is known as the
IDI (Indentation Distance Increase) and will be converted by a computer to BMS. In order to obtain accurate results,
there will be 10 measurements made per subject but the probe will only be adjusted 0.2mm from the initial indentation
site for each additional measurement. Also, the probe will not be lifted out of the periosteum, just out of the bone for
the additional measurements. This procedure has been well-studied in humans with no complications observed to date
in 400 people who have undergone the microindentation procedure. The site of microindentation will be covered with a
bandage and subjects should be able to resume their regular daily activities immediately. The Principal Investigator will
be responsible for receiving the device and will have proper accountability, handling, and storage of the OsteoProbe®.
We will get one shipment which will include the device and the probes once the study is approved. The probes will be
discarded in sharps disposal bins (red bins). The OsteoProbe® handheld device and the individual probes will be
received by the Principal Investigator. There will only be one OsteoProbe® device from the company that will be sent
to CUMC one time in the beginning of the study. The probes themselves will come individually packaged with a lot
number that we will record for each subject. Each subject will also be assigned a subject number consisting of first
initial-last initial and three digit study number (ie 001). The probes will be single use and will be discarded in a sharps
disposal bin (red bin) located at the site of the procedure. Devices will be handled only by individuals listed on the
protocol and the microindentation will only be performed by the study physicians, Drs. Starr and Rubin. We will receive
one probe per subject so the probes will be discarded after each use. While the probes are clean, they are not sterile
so we will sterilize them with steam autoclaving, which will be performed through New York Presbyterian Hospital in
accordance with hospital standards for sterilizing medical equipment. The OsteoProbe® itself will be cleaned before
and after each use with alcohol prep pads.
The OsteoProbe® will be stored at room temperature in a carrying case that has a built-in soft pouch to protect the
device from damage. The probes will be stored at room temperature. The carrying case and the OsteoProbe® will be
kept in a locked office that only the study personnel will have access to. The probes will be used one time per subjects
and will be placed into sharps disposal bins available in the exam rooms where the microindentation is to be
performed.
 
 
Add an individual entry for each human specimen type that will be collected or utilized for the proposed study.
For each specimen type, indicate the source or sources from which you will obtain the specimens.
 
Biological Specimens
IRB-AAAR5451
Page 14 of 30
10/02/2019

The use of specimens for research purposes may require that informed consent (or a waiver, if applicable) and
HIPAA Authorization (or a waiver, if applicable) be obtained from subjects.
 
Type:
Other
Bone biopsy
 
Pathology approval may be necessary if the project includes the collection of specimens that will be collected
from a procedure that is conducted for, or will potentially involve, diagnostic information. The Pathology
request form can be found at the following link:
https://research.columbia.edu/sites/default/files/content/HRPO/BlankPathologyIRBApprovalForm.doc
 
Source:
[x] From Columbia and/or NYP Subjects/Patients or Repositories managed by Columbia
Select all that apply to this specimen type:
[x] Specimens will be prospectively collected specifically for this research.
[  ] Residual specimens from clinical care that would otherwise be discarded have been or will be collected.
[  ] Specimens to be analyzed will be (or have been) collected from a commercial source.
[  ] Specimens to be analyzed will be (or have been) collected under a separate CU IRB-approved protocol; this could
be an approved research repository protocol.
[  ] From Non-Columbia/NYP Subjects/Patients or Repositories not managed by Columbia
Description of Specimen and Method of Obtaining:
Percutaneous transiliac crest bone biopsy will be obtained. 
Indicate the manner in which the specimens will be labeled:
[  ] Specimens will be labeled with direct identifiers
[x] Specimens will be labeled with a code and the research team has the key and can link specimens to direct identifiers.
This code would be considered an indirect identifier
[  ] The identifiers will be removed prior to the receipt of the specimens by Columbia researchers and no link will remain
[  ]  Specimens were originally collected without identifiers
 
If specimens are collected or received at any point in time as with direct or indirect identifiers by the current
researchers, then the specimens are considered to be identifiable, and the requirements for Informed Consent (or
a waiver, if applicable) and HIPAA Authorization (or a waiver, if applicable) apply. The necessary information will
need to be included in the respective sections of this Rascal submission.
Type:
Blood
Source:
[x] From Columbia and/or NYP Subjects/Patients or Repositories managed by Columbia
Select all that apply to this specimen type:
[x] Specimens will be prospectively collected specifically for this research.
[  ] Residual specimens from clinical care that would otherwise be discarded have been or will be collected.
[  ] Specimens to be analyzed will be (or have been) collected from a commercial source.
[  ] Specimens to be analyzed will be (or have been) collected under a separate CU IRB-approved protocol; this could
be an approved research repository protocol.
[  ] From Non-Columbia/NYP Subjects/Patients or Repositories not managed by Columbia
Description of Specimen and Method of Obtaining:
Blood will be collected by research coordinators using vacutainers and butterfly needles.
IRB-AAAR5451
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Indicate the manner in which the specimens will be labeled:
[  ] Specimens will be labeled with direct identifiers
[x] Specimens will be labeled with a code and the research team has the key and can link specimens to direct identifiers.
This code would be considered an indirect identifier
[  ] The identifiers will be removed prior to the receipt of the specimens by Columbia researchers and no link will remain
[  ]  Specimens were originally collected without identifiers
 
If specimens are collected or received at any point in time as with direct or indirect identifiers by the current
researchers, then the specimens are considered to be identifiable, and the requirements for Informed Consent (or
a waiver, if applicable) and HIPAA Authorization (or a waiver, if applicable) apply. The necessary information will
need to be included in the respective sections of this Rascal submission.
 
 
On the General Information page you have indicated that the protocol version associated with the use of this
medical device is as follows: 1
 
Please note that a Protocol Version # is required for protocols using a medical device, and you will not be
allowed to submit this protocol until the Protocol Version # field is complete. Please ensure that the Protocol
Version # is completely and accurately reported on the General Information page. 
 
Please enter the requested information for each device that is the object of the study or is being used because it
is relevant to the aims of the protocol, whether the medical device is not yet FDA-approved [i.e., is
investigational] or is an approved device that is being used in an investigational manner (i.e., off-label use is
being studied). 
 
Note that the questions apply only to devices used in clinical investigations or protocols that involve a
Humanitarian Use Device. Emergency use of a device that is not yet FDA-approved is not a clinical investigation,
and a submission in Rascal may not be required. Please contact the IRB for assistance if emergency use of a
device that is not yet FDA-approved is being considered: (212)305-5883. 
 
Device name:
AGE Reader
Device description:
The AGE Reader is a desktop device that uses the characteristic fluorescent properties of certain AGEs to estimate the
level of AGE accumulation in the skin by measuring autofluorescence of the skin at the forearm.  
Device Model/Version #:
not applicable
Phase of Study:
Feasibility
Manufacturer Information
Is the device a Humanitarian Use Device (HUD)?
Devices
Name:
DiagnOptics Technologies BV
Address:
abc
Contact information:
abc
IRB-AAAR5451
Page 16 of 30
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No
Is the device FDA-approved and used in accordance with its labeling?
No
An Investigational Device Exemption (IDE) may be required.
Select Category:
Not FDA-approved
Provide plans for storage, control and accounting of the device:
Device is stored in a locked cabinet in a locked office in the HP building, room 945. Only Drs. Starr and Rubin have
access to the device as well as coordinators.
Is an FDA-issued Investigational Device Exemption (IDE) required?
No. This is a Nonsignificant Risk device (21 CFR 812.2(b)).
Will a representative of the Sponsor/Manufacturer be involved with the use of the device at Columbia/ NYPH, e.g.,
for training purposes?
No
Device name:
OsteoProbe®
Device description:
The osteoProbe® is a stainless steel handheld device slightly larger than a highlighter with three component parts: an
impact generation mechanism, a displacement transducer and a probe. The probe has a tip diameter of approximately
375m and a tip sharpness radius of less than 10m. The operator uses one hand to press the device through the skin at
the anterior tibia until it sinks slightly into the bone. At this point, the instrument is full compressed and this causes the
impact.
Device Model/Version #:
not applicable
Phase of Study:
Feasibility
Manufacturer Information
Is the device a Humanitarian Use Device (HUD)?
No
Is the device FDA-approved and used in accordance with its labeling?
No
An Investigational Device Exemption (IDE) may be required.
Select Category:
Not FDA-approved
Provide plans for storage, control and accounting of the device:
Device is stored in a locked cabinet in a locked office in the HP building, room 945. Only Drs. Starr and Rubin have
access to the device as well as coordinators.
Is an FDA-issued Investigational Device Exemption (IDE) required?
No. This is a Nonsignificant Risk device (21 CFR 812.2(b)).
Will a representative of the Sponsor/Manufacturer be involved with the use of the device at Columbia/ NYPH, e.g.,
for training purposes?
No
Name:
Active Life Scientific, Inc.
Address:
32 Anacapa St, suite D, Santa Barbara, USA, 93101, 805-770-2600,
Davis@activelifescientific.com
Contact information:
Davis Brimmer
IRB-AAAR5451
Page 17 of 30
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On the General Information page you have indicated that the protocol version associated with the use of this
drug/biologic is as follows: 1
 
Please note that a Protocol Version # is required for protocols using a drug or biologic, and you will not be
allowed to submit this protocol until the Protocol Version # field is complete. Please ensure that the Protocol
Version # is completely and accurately reported on the General Information page.
 
List each drug or biologic that will be administered as the object of the protocol or is being used because it is
relevant to the aims of the research protocol. This applies whether the drug/biologic is not yet FDA-approved
(i.e., is investigational), is FDA approved and used in accordance with its labeling, or is an approved product that
is being used in an investigational manner (i.e., off-label use is being studied).
 
Note that the questions apply only to drugs used in clinical investigations. Emergency use of a drug that is not
yet FDA-approved is not a clinical investigation, and a submission in Rascal may not be required. Please contact
the IRB for assistance if emergency use of a drug or biologic that is not yet FDA-approved is being considered:
(212) 305-5883.
 
Name:
Pyridoxamine Dihydrochloride 
Dose:
200mg Orally twice a day
Study phase:
Phase 2
Manufacturer Information
Route of administration:
Oral
Is the drug/biologic FDA-approved and used in accordance with its labeling?
No
Select a category:
Not FDA-approved
Does the Use of the drug/biologic require an Investigational New Drug (IND) or Biological IND (BB-IND)
application?
NO – this use is exempt.
Since you have indicated that the drug/biologic is either FDA approved but being used outside of its
approved indication, or not FDA-approved, an IND is required unless the clinical investigation meets
criteria to be exempt from the IND requirements. Please choose the regulatory category for exemption from
the IND requirements that applies to your study.
21 CFR 312.2(b)(1) criteria met - This is a clinical investigation of a drug product that is lawfully marketed in the
United States and all the following apply: (i)The investigation is not intended to be reported to FDA as a well-
Drugs/Biologics
Name:
LifeLink Pharmaceuticals
Address:
LifeLink, P.O. Box 1299, Grover Beach, CA 93483-1299
Contact information:
+1(888)433-5266
IRB-AAAR5451
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Street, BT 2213 Troy NY 12180-3590 to be store and use for future research. 
Describe who will have access to the stored data and/or specimens.
Drs. Mishaela Rubin and Jessica Starr.  
[  ]Some or all data/specimens will be released to a non-Columbia entity for future use and Columbia researchers will
not have direct control. 
 
 
Will a contrast agent (e.g. gadolinium) be used in conjunction with radiation exposure that goes beyond the
parameters established for the applicable standard of care (SOC), or will a contrast agent be administered for
research purposes only? 
No
 
 
For each type of radiation exposure (e.g., ionizing: CT, X-ray; non-ionizing: MRI), identify the procedure and
whether the administration (e.g., radiation dosage, number or type of scans) is clinically indicated and in
accordance with the parameters established for the applicable standard of care (SOC), or is "beyond" these
parameters (i.e., includes procedures or exposure for research purposes only). 
 
 
 
Procedure(s) Involving Ionizing Radiation
 
 
Procedure(s) Involving Non-Ionizing Radiation
No data to display
 
 
Recruitment:
 
Describe how participants will be recruited:
Subjects will be recruited from Dr Starr's practice, which includes post-menopausal women with T2D, phone calls to the
previous bone and diabetes study participants (protocol AAAE1078, see script attached) and through flyers that will be
hung at CUMC (see attached flyer). Spanish participants will be enrolled the same way in their preferred language, as Dr
Starr is fluent in Spanish and both the script and flyer will be translated by a certified Columbia University translator after
their respective English versions are approved. In addition, we will be using social media. We will post on websites the
identical text that is in the approved flyer. Finally, we will do mailings to women age 65 or older with HgbA1c 6.5% or
higher who will be found in the electronic medical record (TRAC request at   https://webapps.nyp.org/trac), using the
Imaging Procedures/Radiation Therapy
Procedure
The exposure to:
DEXA Scan
Beyond that established for the applicable SOC
Recruitment And Consent
IRB-AAAR5451
Page 20 of 30
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mailing letter and return postcard.
 
Select all methods by which participants will be recruited:
[  ]  Study does not involve recruitment procedures
[x]  Person to Person
[  ]  Radio
[  ]  Newspapers
[x]  Direct Mail
[x]  Website
  URL: https://newyork.craigslist.org/
[  ]  Email
[  ]  Television
[x]  Telephone
[x]  Flyer/Handout
[  ]  Newsletter/Magazine/Journal 
[  ]  ResearchMatch
[  ]  CUMC RecruitMe
 
Additional Study Information: Please add a description of your study as you would like it to be
displayed on the RecruitMe website.
  
Informed Consent Process:
 
Informed Consent Process, Waiver or Exemption: Select all that apply
 
[x]  Informed consent with written documentation will be obtained from the research participant or appropriate
representative.
 
Documentation of informed consent is applicable to:
The study in its entirety
 
Identify the portion of the study (e.g., prospective portion, focus groups, substudy 2) or
subject population for which documentation of consent will be obtained::
 
Documentation of participation will be obtained from::
[x]  Adult participants
[  ]  Parent providing permission for a child's involvement
[  ]  Legally Authorized Representatives (LARs)
 
Describe how participants' written consent will be obtained:
Participants will read and choose to sign the consent form if they are willing to participate. Investigators
Drs. Starr and Rubin will be available to answer any study-related questions subjects may have. Dr. Starr
is fluent in Spanish.
 
[  ]  Informed consent will be obtained but a waiver of written documentation of consent (i.e., agreement to
participate in the research without a signature on a consent document) is requested.
 
IRB-AAAR5451
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[  ]  A waiver of some or all elements of informed consent (45 CFR 46.116) is requested.
 
[  ]  Planned Emergency Research with an exception from informed consent as per 21 CFR 50.24.
 
[  ]  Informed consent is not required; this is exempt research.
  
Subject Language
Enrollment of non-English speaking subjects is expected.
 
Languages anticipated:
Spanish
 
As you plan on enrolling non-English speaking subjects, administrative IRB approval of the
translated documents (e.g., consent, recruitment materials, questionnaires) in the above selected
languages are required. Please see the IRB's policy on the Enrollment of Non-English Speaking
Subjects in Research for further details
 
(http://www.cumc.columbia.edu/dept/irb/policies/documents/Nonenglishspeakingsubjects.Revised.F
INALDRAFT.111909.website.doc).
  
Capacity to Provide Consent: 
 
Do you anticipate using surrogate consent or is research being done in a population where capacity to
consent may be questionable? 
No
 
 
Research Question(s)/Hypothesis(es):
 Specific Aim 1: Study the effect of pyridoxamine on the formation of new bone in older T2D patientsWe will
compare the change in bone formation in response to pyridoxamine vs. placebo given for 12 months.  We 
expect that pyridoxamine will increase serum P1NP levels in older T2D.  Furthermore, we expect that those
with milder T2D and lower AGEs will display a greater response magnitude.  These results should provide
preliminary data for future studies on the potential use of pyridoxamine as a specific therapeutic for diabetic
bone fragility.Specific Aim 2: Identify the effect of pyridoxamine on bone material strength in older
T2D patients. We hypothesize that, by preventing new glycation of collagen, pyridoxamine as an
intervention will reverse the deterioration of cortical bone material strength, a characteristic feature of
diabetic bone fragility. To determine whether pyridoxamine given to older T2D patients positively affects
bone material properties and strength, we will compare, as in Specific Aim 1, pyridoxamine vs. placebo
given for 12 months, but with BMSi as the measured endpoint. We expect to identify a beneficial effect of
pyridoxamine on BMSi, with a greater response when baseline AGEs are low.  These results, together with
those from Specific Aim 1, should provide preliminary data for a clinical trial of pyridoxamine in T2D and
lead to its investigation as a mechanism-based therapeutic strategy for diabetic bone fragility.
  
Scientific Abstract:
Research Aims & Abstracts
IRB-AAAR5451
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At least 25% of Americans over the age of 65 have type 2 diabetes (T2D), which, in addition to its well-
recognized complications, is accompanied by a high fracture risk, particularly in elderly patients.  Standard
explanations, namely low bone mass and high bone turnover, do not explain how T2D adversely impacts
the aging skeleton. Rather, low bone turnover, specifically reduced formation of new bone, likely
predisposes to a high fracture risk. This is compounded by altered material properties of bone that together
diminish bone strength and increase its propensity to fracture. Both etiologies – reduced bone formation
and altered bone material properties – are increasingly thought to arise from the accumulation of advanced
glycation endproducts (AGEs). Hence, preventing the accumulation of AGEs in bone tissue in T2D patients
is a potential therapeutic strategy with likely effects in reversing bone fragility in T2D. Our preliminary data
show strong correlations between AGE accumulation and both bone formation and bone material properties
 (Furst et al. JCEM, 2016: PMCID: 4891790, IRB protocol AAAE1078).One novel intervention directed to
the etiologic culprit, AGE, is pyridoxamine, a naturally occurring and structurally distinct metabolite of
vitamin B6 pyridoxal phosphate. Preclinical data show that pyridoxamine has specific molecular features
which provide a unique multi-pronged effect to inhibit glycation reactions and the formation of AGEs.
Pyridoxamine is also a potent inhibitor of AGE accumulation and improves bone material properties in
diabetic animals.  Notably, while it also reduces AGEs in patients with T2D with nephropathy, there are no
clinical data on possible skeletal benefits in T2D. Our study will explore the changes in bone formation,
bone material strength and AGE accumulation over a one-year period during which a subset of
postmenopausal women with T2D will be treated with pyridoxamine.  This study has important ramifications
for offering a novel treatment to preserve or improve skeletal health in postmenopausal women with T2D.
  
Lay Abstract:
 Type 2 Diabetes Mellitus (T2DM) has become one of the most important diseases of our time. 
Recent research shows that diabetes has negative effects on bones and that people with diabetes
might be more likely to break a bone.  We don't know the reasons for this, but we suspect that
normal bone replacement is slowed down in diabetes and this could slow down the growth of new
bone.  It is possible that the normal bone material becomes weaker because sugar-related
components ("Advanced Glycation Endproducts") are making the bone more brittle.  We have
shown in past research that people who have type 2 diabetes are more likely to have both weaker
bone with lower "bone material strength" and also higher levels of sugar-related components
("Advanced Glycation Endproducts").  This study will focus on attempting to lower the sugar-
related components ("Advanced Glycation Endproducts") by treating a group of patients with type
2 diabetes with a B vitamin, known as vitamin B6 or pyridoxamine for one year.  We will compare
post-menopausal women both before and after pyridoxamine use and study them in terms of
different bone features based on blood tests, bone imaging, a bone indentation test and a
measurement of sugar-related components in the skin.  This study will help to clarify if using
pyridoxamine helps improve bone strength in women with diabetes.
 
 
Abbreviated Submission:
The IRB has an abbreviated submission process for multicenter studies supported by industry or NIH
cooperative groups (e.g., ACTG, HVTN, NCI oncology group studies, etc.), and other studies that have a complete
stand-alone protocol. The process requires completion of all Rascal fields that provide information regarding
Risks, Benefits & Monitoring
IRB-AAAR5451
Page 23 of 30
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local implementation of the study. However, entering study information into all of the relevant Rascal fields is not
required, as the Columbia IRBs will rely on the attached stand-alone (e.g., sponsor's) protocol for review of the
overall objectives. .
If you select the Abbreviated Submission checkbox and a section is not covered by the attached stand-alone
protocol, you will need to go back and provide this information in your submission. 
  
Potential Risks:
Provide information regarding all risks to participants that are directly related to participation in this protocol,
including any potential for a breach of confidentiality. Risks associated with any of the items described in the
Procedures section of this submission should be outlined here if they are not captured in a stand-alone protocol.
Risks of procedures that individuals would be exposed to regardless of whether they choose to participate in this
research need not be detailed in this section, unless evaluation of those risks is the focus of this research. When
applicable, the likelihood of certain risks should be explained and data on risks that have been encountered in
past studies should be provided.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
Potential risks of study participation include venipuncture, radiation exposure from DXA, impact
microindentation and the bone biopsy. The skin autofluorescence protocol does not involve risk.
Venipuncture: Risks include pain, bleeding, bruising, infection and inflammation at the site. The
risks of venipuncture will be minimized by having trained, experienced professional staff to obtain
all blood samples.Radiation: Each patient will have 2 DXA exam. The radiation exposure for DXA
(spine, one hip and forearm) using the Hologic QDR4500 (fast scan) is 14.9 µSv. This compares to
2400 µSv natural background in a year, 8000 µSv for a standard chest CT, 450 µSv for a
mammogram, and 60 µSv for a round-trip transcontinental plane flight. The total radiation exposure
is less than the same relative risk as <1 month of natural background radiation and will be well
below the maximal acceptable dose for normal subjects. All subjects will be counseled in detail
about the amount of radiation that they will receive as a result of participation in the study as part
of Informed Consent procedures.Impact micoindentation: The procedure causes minimal
discomfort (only during the local anesthesia injection) and no complications have been observed to
date. Patients who have a significant skin disorder, bruising, local edema, or infection, as well as
those undergoing treatment for blood clots or severe coagulation defects will be excluded.Bone
biopsy: In 10 randomly selected Caucasian patients with high (2.6; n=5) and low (2.0; n=5) skin
autofluorescence levels, bone biopsies will be performed prior to randomization. The biopsy
advanced glycation endproduct (AGE) assay will precisely quantify the degree of collagen
glycation in the cancellous and cortical compartments with a fluorometric assay. The risks of bone
biopsy includes the risks of conscious sedation and the risks of the biopsy itself. Conscious
sedation will be offered to subjects who have a bone biopsy in order to minimize anxiety, provide
pain relief and diminish recall. Patients receiving conscious sedation may have brief transient loss
of protective reflexes. Risks will be minimized by complying with all procedures as required in the
Columbia University Medical Center Policies and Procedures Manual. Specifically, all nurses and
physicians involved in performing bone biopsies will have certification in Basic Life Support and
Advanced Cardiac Life Support. The procedure will be conducted in an outpatient surgery suite,
which has a stocked "crash cart"; vital signs (including O2 saturation) will be monitored at regular
intervals during and after the procedure.  Complications from the biopsy itself are very unusual, but
could include cutaneous nerve entrapment, bleeding, fracture of the iliac wing and prolonged
IRB-AAAR5451
Page 24 of 30
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discomfort. Our experience has been that the aforementioned complications do not occur when
bone biopsy is performed correctly. Infections at the biopsy site have occurred in only 2 of more
than 1000 biopsy procedures done at Columbia. The sterile environment of the operating room or
specialized surgical suite is very helpful in this regard. More commonly, there will be a bruise at the
site or discomfort that persists for only a few days. Close follow-up by our research nurse identifies
any problems after the procedure.Administration of pyridoxamine dihydrochloride: 
Pyridoxamine dihydrochloride will be administered at a dose of 200 mg PO BID. Randomization
will be done by the Research Pharmacy with a block scheme stratifying for race. Study drug will be
dispensed by the Research Pharmacy. The dose we are using is available as an over-the-counter
supplement. We have considered the safety of our regimen. Excessive ingestion of vitamin B6
(pyridoxine) when used as a dietary supplement at doses up to 2 g/day has been reported to
cause a neurotoxic syndrome in patients as characterized by paresthesias, muscle weakness and
numbness 1.  In contrast, no neurological or behavioral signs of toxicity have been reported, to the
best of our knowledge, following administration of pyridoxamine dihydrochloride. In a large (n=317)
clinical trial of pyridoxamine, doses that are similar (150 mg po bid and 300 mg po bid, for 52
weeks) to our planned dose of 200 mg po bid for 52 weeks were used 2. In that study, there was
no association between pyridoxamine and serious adverse events.  Recently, administration of up
to 200 mg/kg/day in Sprague-Dawley rats of pyridoxamine dihydrochloride via IV infusion for seven
consecutive days was not associated with any treatment-related findings including gross or
microscopic findings in the nervous system (brain, spinal cord, spinal nerve roots/ganglia, and
peripheral nerves), liver, kidneys, heart, spleen, thymus, pancreas, or the catheter emptying site.
Based on those data, the no observed adverse effect level in Sprague-Dawley rats was
determined to be 200 mg/kg/day 3. To address the unlikely issue of vitamin B6 neurotoxicity, at
each study visit neurological symptoms will be reviewed and a full neurologic exam will be
performed. Any neurologic findings will be immediately reported to the Medical Monitor and will be
reviewed with the Data Safety and Monitoring Board.1. Dalton K, Dalton MJ. Characteristics of
pyridoxine overdose neuropathy syndrome. Acta Neurol Scand. 1987;76(1):8-11. PubMed PMID:
3630649.2. Lewis EJ, Greene T, Spitalewiz S, Blumenthal S, Berl T, Hunsicker LG, et al. Pyridorin
in type 2 diabetic nephropathy. J Am Soc Nephrol. 2012;23(1):131-6. doi:
10.1681/ASN.2011030272. PubMed PMID: 22034637; PubMed Central PMCID:
PMCPMC3269925.3. Sullivan DW, Jr., Peterson RC, Mujer CV, Gad SC. A 7-day intravenous
toxicity study and neurotoxicity assessment of pyridorin in Sprague-Dawley rats. Hum Exp Toxicol.
2016. doi: 10.1177/0960327116661023. PubMed PMID: 27507076. 
  
Potential Benefits:
Provide information regarding any anticipated benefits of participating in this research. There should be a
rational description of why such benefits are expected based on current knowledge. If there is unlikely to be
direct benefit to participants/subjects, describe benefits to society. Please note that elements of participation
such as compensation, access to medical care, receiving study results, etc. are not considered benefits of
research participation.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 There is no direct benefit to subjects. The benefit to society may be additional information
about potential treatment for the deleterious effects of diabetes on bone.
  
IRB-AAAR5451
Page 25 of 30
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Alternatives:
If this research involves an intervention that presents greater than minimal risk to participants, describe available
alternative interventions and provide data to support their efficacy and/or availability. Note, participants always
have the option not to participate in research.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 The alternative would be for the subject not to participate.
  
Data and Safety Monitoring:
Describe how data and safety will be monitored locally and, if this is a multi-center study, how data and safety
will be monitored across sites as well.
[  ]  Abbreviated Submission - This information is included in an attached stand-alone protocol. Proceed to the next
question
 We will be using a multi-server user that has been registered and certified by CUMC IT (System
ID number 3924; IP Address: 10.171.8.150) to store and collect study data and SSN information.
The server will be accessed through password protected computers only which are encrypted(no
laptops, no portable data drives). We will have a Data and Safety Monitoring Board (DSMB)
constitute of  2 endocrinologists and 1 statistician; we will meet once a year and have a conference
call every 6 months or more often if necessary.  
 
 
Unless otherwise noted, the information entered in this section should reflect the  number of subjects enrolled or
accrued under the purview of Columbia researchers, whether at Columbia or elsewhere.
Target enrollment:
70
Number enrolled to date:
11
Number enrolled since the last renewal or, if this is the first renewal, since the initial approval:
11
Number anticipated to be enrolled in the next approval period:
52
Does this study involve screening/assessment procedures to determine subject eligibility?
Yes
Target accrual:
52
Number accrued to date:
0
Number accrued since the last renewal or, if this is the first renewal, since the initial approval:
11
Number anticipated to be accrued in the next approval period:
52
Of the number of subjects enrolled, or the number accrued for interventional studies with a screening process:
How many remain on the study?
11
How many are off study?
Subjects
IRB-AAAR5451
Page 26 of 30
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0
How many completed the study?
0
Have any withdrawn of their own initiative?
No
Have any been removed by PI?
No
Have any been lost to follow-up?
No
Have any died while on study?
No
Have any subject complaints been received?
No
Is this a multi-center study?
No
Does this study have one or more components that apply to a subset of the overall study population (e.g. Phase
1/2, sub-studies)?
Yes
Of the number enrolled, or the number accrued for interventional studies with a screening process, indicate:
Population Gender
Population Age
Population Race
Population Ethnicity
Vulnerable Populations as per 45 CFR 46:
Will children/minors be enrolled
No
Will pregnant women/fetuses/neonates be targeted for enrollment?
No
Will prisoners be targeted for enrollment?
Name/Procedure
Target enrollment
Enrolled to date
Enrollment Status
Bone Biopsy
10
3
Open to enrollment or
ongoing review of
records/specimens
Females
Males
Non Specific
100%
0%
0%
0-7
8-17
18-65
>65
Non Specific
0%
0%
0%
100%
0%
American
Indian/Alaskan
Native
Asian
Native Hawaiian
or Other Pacific
Islander
Black or African
American
White
More than One
Race
Non-Specific
0%
0%
0%
18%
82%
0%
0%
Hispanic or Latino
Not Hispanic or Latino
Non-Specific
45%
0%
55%
IRB-AAAR5451
Page 27 of 30
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No
Other Vulnerable Populations:
[  ]Individuals lacking capacity to provide consent
[  ]CU/NYPH Employees/Residents/Fellows/Interns/Students
[  ]Economically disadvantaged
[  ]Educationally disadvantaged
[x]Non-English speaking
Please ensure that your plan to enroll subjects in their primary language is described on the Informed
Consent page.
[  ]Other Vulnerable populations
[  ]None of the Populations listed above will be targeted for Enrollment
Subject Population Justification:
We are enrolling post-menopausal women with Type 2 diabetes to assess the effects of pyridoxamine on the interaction
between bone material strength and AGEs accumulation. We are enrolling both English and Spanish-speaking women as
the predominant minority group at CUMC are women from Latin America.
Does this study involve compensation or reimbursement to subjects?
Yes
Describe and justify reimbursement/compensation:
We are reimbursing $225 for completion of the one year study. We feel this amount compensates study subjects for
their time and effort to be in the study.
If subjects chose to have the bone biopsy, they will be compensated an additional $250 as this is an invasive
procedure and requires an additional study visit.
Are subjects eligible for compensation of $600 or more in a calendar year?
No
 
 
 
 
 
 
HazMats
Type
Number
Date Created
Principal Investigator
Radiation Safety (Appendix
H)
APH-AAAW7271
08/23/2017
Maximo Gomez Almonte
(meg2230)
Attached Attestation
Type
Principal Investigator
Date Created
C
Mishaela Rubin
09/13/2018
Attached HIPAA Forms
Number
Type
Title
Status
AAAO0049
A
B6 study - Spanish
Approve
AAAM7301
A
Form A Updated
Approve
IRB-AAAR5451
Page 28 of 30
10/02/2019

 
 
 
 
Number
Type
Title
Status
AAAN9051
D
B6 Study
Approve
Attached Consent Forms
Number
Copied From
Form Type
Title
Active/InActive
Initiator
AABJ4500
AABJ4500
Consent
Consent for Bone
Biopsy sub-study
Active
Xiomara Javier-Espinal
(xij2000)
AABK9700
AABJ4550
Consent
B6 and
microindentation
consent
Active
Xiomara Javier-Espinal
(xij2000)
Documents
Archived
Document
Identifier
Document Type
File Name
Active
Stamped
Date Attached
Created By
No
AAAR5451 B6
ICF Spa
Consent
Form/Addendum
AAAR5451 B6
ICF Spa.pdf
N
02/28/2018
Maximo Gomez
Almonte
(meg2230)
No
AAAR5451 B6-
BBx ICF Spa
Consent
Form/Addendum
AAAR5451 B6-
BBx ICF Spa.pdf
Y
02/28/2018
Maximo Gomez
Almonte
(meg2230)
No
B6  ICF consent
form tracket
changes
9.4.2018
Consent
Form/Addendum
(tracked)
B6  ICF consent
form tracket
changes
9.4.2018.pdf
Y
09/12/2018
Xiomara Javier-
Espinal (xij2000)
No
Rubin_applicatio
nimage_ASSIST
6
Funding/Grant
Application/Subc
ontract
Rubin_applicatio
nimage_ASSIST
6.pdf
Y
09/29/2017
Maximo Gomez
Almonte
(meg2230)
No
Brochure AGE
Reader
Investigator
Brochure/Packag
e Insert/Device
Manual
Brochure AGE
Reader mu
English (3).pdf
Y
10/18/2017
Lisa Lotwin
(ls432)
No
Brochure_AGE_
Reader_mu
Investigator
Brochure/Packag
e Insert/Device
Manual
Brochure_AGE_
Reader_mu.pdf
Y
10/09/2017
Maximo Gomez
Almonte
(meg2230)
No
Diab-
spot_brochure_S
ept_2011_EN
Investigator
Brochure/Packag
e Insert/Device
Manual
Diab-
spot_brochure_S
ept_2011_EN.pdf
Y
10/09/2017
Maximo Gomez
Almonte
(meg2230)
No
OsteoProbe RUO
User's Guide
Investigator
Brochure/Packag
e Insert/Device
Manual
OPG-001_A
(OsteoProbe
RUO User's
Guide v1 0).pdf
Y
10/18/2017
Lisa Lotwin
(ls432)
No
Osteoprobe
Qualifications
Investigator
Brochure/Packag
e Insert/Device
Manual
Osteoprobe
Qualifications.pdf
Y
10/09/2017
Maximo Gomez
Almonte
(meg2230)
No
OsteoProbe RUO
OnePager
Investigator
Brochure/Packag
e Insert/Device
Manual
OsteoProbe RUO
OnePager_Dr
Mishaela Rubin
of Columbia
Univ.pdf
Y
10/18/2017
Lisa Lotwin
(ls432)
No
OsteoProbe User
Instructions
Investigator
Brochure/Packag
e Insert/Device
Manual
OsteoProbe User
Instructions.pdf
Y
10/09/2017
Maximo Gomez
Almonte
(meg2230)
No
PrimAGE-o
Investigator
Brochure/Packag
e Insert/Device
Manual
PrimAGE-o.pdf
Y
10/09/2017
Maximo Gomez
Almonte
(meg2230)
IRB-AAAR5451
Page 29 of 30
10/02/2019

Archived
Document
Identifier
Document Type
File Name
Active
Stamped
Date Attached
Created By
No
Tetracycline_Lab
el
Investigator
Brochure/Packag
e Insert/Device
Manual
Tetracycline_Lab
el.pdf
Y
10/23/2017
Maximo Gomez
Almonte
(meg2230)
No
Table 1 Protocol
tracked changes
9.5.2018
Other
Table 1 Protocol
tracked changes
9.5.2018.pdf
Y
09/12/2018
Xiomara Javier-
Espinal (xij2000)
No
B6 Postcard-
SPANISH
Recruitment
Material
AAAR5451 B6
Postcard-
SPA.pdf
Y
06/22/2018
Rukshana
Majeed (rm3324)
No
Spanish
Brochure
Recruitment
Material
AAAR5451
Brochure B6-
SPA.pdf
Y
06/22/2018
Rukshana
Majeed (rm3324)
No
AAAR5451
Diabetes bone
flyer Spa
Recruitment
Material
AAAR5451
Diabetes bone
flyer Spa.pdf
Y
02/28/2018
Maximo Gomez
Almonte
(meg2230)
No
Mailing Letter in
Spanish
Recruitment
Material
AAAR5451 Vit 6
Letter-
SPANISH.pdf
Y
06/22/2018
Rukshana
Majeed (rm3324)
No
B6 diabetes bone
flyer
Recruitment
Material
B6 diabetes bone
flyer.pdf
Y
01/11/2018
Maximo Gomez
Almonte
(meg2230)
No
Brochure
5.16.2018
Recruitment
Material
brochure 5-16-
18.pdf
Y
05/16/2018
Rukshana
Majeed (rm3324)
No
mailing about
study 5-16-18-
updated
Recruitment
Material
mailing about
study 5-16-18.pdf
Y
05/23/2018
Rukshana
Majeed (rm3324)
No
Mailing letter
5.16.2018
Recruitment
Material
mailing about
study 5-16-18.pdf
N
05/16/2018
Rukshana
Majeed (rm3324)
No
Postcard
Recruitment
Material
postcard with
mailing 5-16-
18.pdf
Y
05/16/2018
Rukshana
Majeed (rm3324)
No
Telephone script
for recontacting
subjects for new
Diabetes
Recruitment
Material
Telephone script
for recontacting
subjects for new
Diabetes and
MRR.pdf
Y
09/29/2017
Maximo Gomez
Almonte
(meg2230)
No
B6 ICF Protocol
Tracket Changes
9.4.2018
Standalone/Spon
sor's Protocol
(tracked)
B6 ICF Protocol
Tracket Changes
9.4.2018.pdf
Y
09/12/2018
Xiomara Javier-
Espinal (xij2000)
No
Exercise
Questions v10-1-
17
Study
Material/Instrume
nt
Exercise
Questions v10-1-
17.pdf
Y
10/02/2017
Maximo Gomez
Almonte
(meg2230)
IRB-AAAR5451
Page 30 of 30
10/02/2019