Clinical trial NCT00395538
Conditions: Hypoparathyroidism DiGeorge Syndrome
Keywords: Parathyroid Bone Biopsy Calcium-Sensing Receptor Bone Density Bone Turnover Hypoparathyroidism
Sponsor: National Institute of Dental and Craniofacial Research (NIDCR)
Start date: 2006-10-30; Completion date: 2017-10-04
Enrollment: 46 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Hypoparathyroidism is a rare condition associated with a low level of parathyroid hormone (PTH) in the blood. Hypoparathyroidism can be genetic and show up in childhood, or it can occur later in life. If it occurs later, it is usually due to damage or removal of the parathyroid glands during neck surgery. PTH helps control the amount of calcium in blood, kidneys, and bones. Low levels of calcium in the blood can cause a person to feel sick. It can cause cramping or tingling in the hands, feet, or other parts of the body. A very low blood calcium can cause fainting or seizures.

The standard treatment for hypoparathyroidism is a form of vitamin D (calcitriol) and calcium supplements. Keeping normal blood levels of calcium can be difficult. Sometimes there is too much calcium in the urine even if the calcium levels in the blood are low. High calcium in the kidneys and urine can cause problems such as calcium deposits in the kidney (nephrocalcinosis) or kidney stones. High levels of calcium in the kidney may keep the kidney from functioning normally. Treatment with PTH will replace the hormone you are missing. Your disease may be better controlled on PTH than on calcium and calcitriol.

Researchers at the NIH have conducted prior studies to establish synthetic human parathyroid hormone 1-34 (HPTH) as a treatment for hypoparathyroidism. Other studies have shown that PTH may improve calcium levels in blood and urine. The primary purpose of this research study is to evaluate the effects of synthetic human parathyroid hormone 1-34 (HPTH) replacement therapy on bone in adults and teenagers with hypoparathyroidism.

The study takes 5 (Omega) years to complete and requires 12 inpatient visits to the National Institutes of Health Clinical Center in Bethesda, MD. The first visit will help the study team decide whether you are eligible. This visit will last 2 to 3 days. After taking calcium and calcitriol for 1 - 7 months you will return to the NIH Clinical Center for the baseline visit. The baseline visit is the visit that you will start your PTH; you will also undergo a bone biopsy during the visit. The baseline visit may last 7 to 10 days. You will then take PTH twice a day for 5 years. You will be asked to return to the NIH clinical center every 6 months for 10 follow-up visits. During one of the follow-up visits, you will have a second bone biopsy taken from the other hip. That second biopsy will be done after 1 year, 2 years, or 4 years of taking PTH; the researchers will assign the timing of the second biopsy randomly. You will be asked to go to your local laboratory for blood and urine tests between each follow up visit. At first the blood tests will occur at least once a week. Later, you will need to go to your local laboratory for blood tests at least once a month and urine tests once every 3 months. The local laboratory visits and follow-up visits at the NIH Clinical Center will help the study team determine whether the HPTH treatment is controlling your hypoparathyroidism.

Detailed description:
Objectives

The primary objective of this study is to evaluate the skeletal effects of hormone replacement therapy with HPTH in hypoparathyroidism.

Study Population

This study will enroll up to 69 subjects with physician-diagnosed hypoparathyroidism.\<TAB\>

Design

This study will treat hypoparathyroid individuals with synthetic human PTH 1-34 (HPTH) for up to 5 years, periodically assessing skeletal changes through biochemical markers and iliac-crest bone biopsies, which will allow for ultrastructural, cellular, and molecular analyses.

With respect to HPTH treatment, this study is a single group, within-subjects, repeated measures treatment trial. With respect to all bone biopsy analyses, the design is a parallel group design with each subject allocated to one of the 3 biopsy follow-up times: 1, 2 or 4 years after initiation of HPTH therapy. Post-baseline biopsy timing will be randomly assigned (1:1.2:1.4, respectively) to each subject, stratified by gender and by menopausal status, when relevant. Changes from baseline (time 0) to 1, 2 and 4-years will be compared. Subjects who were on conventional therapy in the former version of the protocol will also be randomized into the new study design. In contrast to new subjects, whose biopsy is performed at the end of the conventional care run-in period, the pre-conventional care biopsy will be used as the baseline for the those subjects entering the new design after having been on conventional care in the older protocol. Because it is not known with certainty what effects duration of time on conventional therapy will have on biopsy results, randomization will also be stratified on status of prior study participation. The subjects who were on HPTH therapy at the time of the protocol redesign are followed as a separate group under this protocol.

Outcome Measures

Primary:

Changes in static and dynamic bone histomorphometry after 1 year, 2 years, and 4 years of HPTH therapy. Primary outcome measurements include:

* Mineralized perimeter
* Bone formation rate
* Cortical width
* Cortical area
* Osteoid width
* Osteoid perimeter
* Mineral apposition rate

Secondary:

Changes in bone mineralization density distribution at 1, 2 and 4 years of HPTH therapy. The specific outcomes that will be measured include:

* Spectral calcium-mean
* Calcium-peak
* Calcium-width

Changes from baseline will be assessed in the following outcomes:

* Biochemical markers of bone metabolism: osteocalcin, bone-specific alkaline phosphatase, collagen cross-linked N-telopeptide.
* Serum and urine calcium; 1,25-OH2-Vitamin D
* Bone density assessed by DXA and quantitative CT
* Nephrocalcinosis by ultrasound and CT
* Fatigue Symptom Inventory
* 6-Minute Walk Test
* SF-36 Health Survey

Tertiary:

Changes in blood chemistries and FGF23, renal mineral handling, and PTH sensitivity with the initiation of HPTH, which include:

* Serum albumin, calcium, phosphorus, magnesium, sodium, potassium, chloride, Total CO2, creatinine, glucose, urea nitrogen, and FGF23
* Urine cAMP, creatinine, phosphorus, calcium, and pH

Arms: arm 1: Subjects are randomized to have the second bone biopsy done 1,2, or 4 years after the start of PTH.
Interventions: intervention 1: PTH 1-34
Intervention descriptions: intervention 1: Given twice daily by subcutaneous

Protocol documents:
SAP_000.pdf: 
Version: SAP_v2.0_2018-06-06_signed.pdf
STATISTICAL ANALYSIS PLAN
06 June 2018
Effects of PTH Replacement on Bone in Hypoparathyroidism
PROTOCOL NUMBER  07-D-0016 
SPONSORED BY
Dr. Rachel Gafni, 
National Institute of Dental and Craniofacial Research
National Institutes of Health
Building 30, Room 228
Bethesda, Maryland 20814
Phone: 301-594-9924
PREPARED BY
Robert James, MS,
Rho, Inc.
The Rho Building,
6330 Quadrangle Drive, Suite 500
Chapel Hill, NC  27517
Telephone:  (919) 408-8000
Fax:  (919) 408-0999
This document is confidential and proprietary to Rachel Gafni, MD, NIDCR.  Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be 
reproduced, published, or otherwise disclosed without the prior written approval of Rachel Gafni, MD, 
NIDCR, except that this document may be disclosed to appropriate Institutional Review Boards under the 
condition that they keep the information confidential.


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DOCUMENT VERSION CONTROL
Version Number
Date
Comments/Changes
0.12
05-Jan-2017
First draft.  This line will be updated to 
version 1.0, when the document is 
finalized.
1.0
17-Feb-2017 
Planned as Final.  Not finalized.
1.2
31-May-2018
Changed the name of the ITT Population 
to Secondary Efficacy Population which is 
more appropriate (Section 4).  
Clarified when the Bone Biospy or 
Secondary Efficacy Analysis Populations 
are used for the efficacy analyses (Section
7.4).
Stated that the 4-year biopsy endpoints 
may be dropped from the bone biopsy 
analyses if they are qualitatively different 
from the 2-year biopsy endpoints. 
(Sections 7.4.1 and 7.4.2).
2.0
06-May-2018
Minor edits. Saved as Final 


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APPROVALS
By signing this document, I indicate that I have reviewed and hereby approve the 
contents, procedures and standards described herein.
Date:
Rachel Gafni, MD, Principal Investigator
Date:
Robert James, MS, Senior Biostatistician III
Date:
Nancy Yovetich, PhD, Principal Research Scientist
+VOF
Rachel I. Gafni -
S
Digitally signed by Rachel I. Gafni -S 
DN: c=US, o=U.S. Government, ou=HHS, 
ou=NIH, ou=People, 
0.9.2342.19200300.100.1.1=0010067536, 
cn=Rachel I. Gafni -S 
Date: 2018.06.06 14:26:22 -04'00'
Robert James
Digitally signed by Robert James 
DN: dc=com, dc=rhoworld, dc=ms, 
ou=Departments, ou=_Users, ou=Blue, cn=Robert 
James, email=robert_james@rhoworld.com 
Date: 2018.06.06 17:17:21 -04'00'
Nancy Yovetich
Digitally signed by Nancy Yovetich 
DN: dc=com, dc=rhoworld, dc=ms, 
ou=Departments, ou=_Users, ou=Blue, cn=Nancy 
Yovetich, email=nancy_yovetich@rhoworld.com 
Date: 2018.06.07 09:05:49 -04'00'


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TABLE OF CONTENTS
LIST OF ABBREVIATIONS ............................................................................................. 5 
1.
PURPOSE OF THIS DOCUMENT............................................................................. 7
2.
PROTOCOL SUMMARY........................................................................................... 8
2.1 Study Objectives .............................................................................................................. 8 
2.2 Overall Study Design and Plan ........................................................................................ 8 
2.3 Study Population.............................................................................................................. 9 
3.
GENERAL ANALYSIS AND REPORTING CONVENTIONS ................................. 10
4.
ANALYSIS POPULATIONS ....................................................................................11
5.
STUDY PATIENTS ..................................................................................................12
5.1 Disposition of Patients ................................................................................................... 12 
5.2 Protocol Deviations ....................................................................................................... 12 
6.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .......................13
7.
EFFICACY EVALUATION .....................................................................................14
7.1 Handling of Dropouts or Missing Data ......................................................................... 14 
7.2 Efficacy Analysis ........................................................................................................... 14 
7.2.1 
Primary Study Endpoints........................................................................14 
7.2.2 
Secondary Study Endpoints ....................................................................15 
7.3 Tertiary Outcome Measures .......................................................................................... 17 
7.3.1 
Changes in blood chemistries..................................................................17 
7.3.2 
Changes in fibrobast growth factor 23 .....................................................17 
7.3.3 
Changes in renal mineral handling and PTH sensitivity.............................17 
7.4 Analysis Methods .......................................................................................................... 17 
7.4.1 
Primary Efficacy Analyses .....................................................................18 
7.4.2 
Secondary Efficacy Analyses..................................................................19 
7.4.3 
Other Efficacy Analyses.........................................................................22 
8.
SAFETY EVALUATION..........................................................................................23
9.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL........................24
10. LIST OF PLANNED TABLES..................................................................................25


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LIST OF ABBREVIATIONS
AjAR
Adjusted apposition rate
BMD 
Bone mineralization density
BMI 
Body mass index
cAMP
Cyclic adenosine monophosphate
Cn.BFR/BS 
Cancellous bone formation rate
Cn.BV/TV 
Cancellous Bone Volume
Cn.MS/BS
Cancellous mineralizing surface (bone surface based)
Cn.MAR
Cancellous bone mineral apposition rate
Cn.O.Th
Cancellous osteoid thickness
CT 
Computed tomography
Ct.Ar 
Total Area of Inner and Outer Cortices
Ct.BFR/BS
Intracortical bone formation rate
Ct.MAR
Intracortical bone mineral apposition rate
Ct.MS/BS
Intracortical mineralizing surface (bone surface based)
Ct.Po.Ar
Total area of cortical porosity
Ct.Po.N
Total Number of Cortical Porosity per mm2
Ct.Th 
Average Thickness of Inner and
Ec.BFR/BS
Endocortical bone formation rate
Ec.MAR
Endocortical bone mineral apposition rate:
Ec.MS/BS
Endocortical mineralizing surface (bone surface based)
Ec.MAR
Endocortical bone mineral apposition rate
Ec.OS/BS
Osteoid surface/bone surface
Ec.O.Th
Endocortical osteoid thickness
ES/BS
Eroded surface  / bone surfac
FGF23
Fibroblast growth factor 23
hPTH
Synthetic human parathyroid hormone 1-34
Ic.BFR/BS 
Intracortical bone formation rate
Ic.MS/BS 
Intracortical mineralizing surface (bone surface based)
MAR
Bone mineral apposition rate
NC/NL
Nephrocalcinosis and Nephrolithiasis


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O.Th
Osteoid Thickness
OS/BS
Osteoid surface / bone surface
PTH
Parathyroid hormone
Tb.BV/TV
Trabecular bone volume
Tb.N 
Trabecular number
Tb.Sp
Trabecular Separation
Tb.Th
Trabecular thickness


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1.
PURPOSE OF THIS DOCUMENT
Several journal publications are expected from the study.  This is an abbreviated statistical 
analysis plan with this document’s primary focus on the statistical methods that will be used for 
the main publication. The safety analyses for this study have already been reported to the DSMB 
and will not be discussed further except to note that the tables and listings generated for the 
DSMB will be provided.


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2.
PROTOCOL SUMMARY
2.1 Study Objectives
The primary objective of this study is to evaluate the skeletal effects of hormone replacement 
therapy with synthetic human parathyroid 1-34 hormone (hPTH) in hypoparathyroidism
2.2
Overall Study Design and Plan
Copied from the protocol: 
This study will treat hypoparathyroid individuals with synthetic human PTH 1-34 (hPTH) for up 
to 5 years, periodically assessing skeletal changes through biochemical markers and iliac-crest 
bone biopsies, which will allow for ultrastructural, cellular, and molecular analyses. 
As revised in April 2010, the “current” protocol involves the recruitment of 36 new subjects (not 
previously enrolled) with hypoparathyroidism and the re-enrollment of qualifying subjects from 
the original protocol who were either on conventional therapy (calcium and calcitriol) or on 
hPTH therapy. All newly enrolled subjects will be placed on conventional therapy for 2 to 6 
months (± 1 month), have a baseline bone biopsy performed at the start of hPTH therapy, and 
have their second biopsy performed after 1, 2, or 4 years of hPTH therapy, with the timing of the 
second biopsy determined by random assignment. The subjects on conventional therapy under the 
previous version of the protocol were randomized to a second biopsy at year 1, 2, or 4; however, 
their pre-conventional therapy biopsy will be used as their baseline biopsy. Subjects who were 
receiving hPTH under the previous version of the protocol are being maintained on hPTH in a 
separate group as a means to continue their care and to describe the effects of hPTH therapy on 
bone and markers of bone metabolism over time. Those subjects will not have another biopsy 
performed. All new and re-enrolled subjects will receive hPTH therapy for a maximum of 5 
years.
Subjects will be initiated on hPTH DWDVWDUWLQJGRVHRIȝJNJGRVHVXEFXWDQHRXVO\WZLFHD
day (study month 0). Subjects currently on hPTH therapy 3 times per day under the previous 
version of the protocol will be placed on hPTH 2 times per day, initially keeping the total daily 
dose the same. Over the 5-year course of hPTH therapy, the subjects will have their blood and 
urine measured repeatedly and evaluated by the study investigators, who will adjust subjects’ 
hPTH dosing according to a standardized algorithm. During hPTH therapy, subjects will visit the 
NIH Clinical Center every 6 months for outcome assessments. At the conclusion of the 5-year 
treatment period, subjects will be transitioned back to conventional care and followed for a 


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minimum of 3 months before returning them to care under their own physicians.  All subjects, 
including those who discontinue hPTH prior to 5 years, will be asked to return for a final, follow-
up visit approximately 6 months after the start of the post-hPTH stabilization phase (i.e., the 
initiation of transition to conventional care).
With a study period of approximately 6 years, the duration of the active phase of the study will be 
9 years. New subjects will have 13 NIH visits, subjects currently on conventional care will have 
12 NIH visits, and subjects currently on hPTH therapy will have up to 9 visits, depending on the 
amount of time they have been treated with hPTH under the previous version of the protocol. 
Additional visits may occur in order to evaluate adverse events.
The study design diagram and the schedule of events may be found in Appendices to the protocol.
2.3
Study Population
Copied from the protocol:
This study will enroll up to 69 subjects with physician-diagnosed hypoparathyroidism.  Under the 
current protocol, 36 new subjects (i.e., not previously enrolled) with physician-diagnosed 
hypoparathyroidism who meet the revised eligibility criteria listed below will be enrolled. 
Previously enrolled subjects who were on conventional therapy for hypoparathyroidism were re-
evaluated under the revised eligibility criteria and re-consented and re-enrolled if they were 
eligible and interested. 
Previously enrolled subjects who were on hPTH therapy were re-consented and allowed to 
continue on hPTH therapy in the current protocol as a separate group that would not enter the 
randomization nor have any additional biopsies performed.  However, they will return to the NIH 
for 6-month follow-up visits and assessments. Those subjects on hPTH at the time of re-consent 
were not re-assessed using the revised criteria, and their study data will be analyzed separately 
from the other subjects’ data. 


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3.
GENERAL ANALYSIS AND REPORTING CONVENTIONS
x
Categorical variables will be summarized using counts (n) and percents (%) and will be
presented in the form n (%).
x
Standard deviations and confidence limits will be reported at 1 more significant digit than
the mean.
x
Order statistics including median, min and max will be reported to the same level of
precision as the original observations.  If any values are calculated to have more significant
digits then the value should be rounded so that it is the same level of precision as the
original data.
x
Following SAS default rules, the median will be reported as the average of the two middle
numbers if the dataset contains even numbers.
x
No preliminary rounding should be performed; rounding should only occur after analysis.
To round, consider digit to right of last significant digit:  if < 5 then round down, if >=5
then round up.
x
All analysis will be performed using the SAS System version 9.4.


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4.
ANALYSIS POPULATIONS
There are 3 Study Cohorts for purposes of analysis:
Cohort 1:  subjects who received hPTH under the original protocol; 
Cohort 2:  subjects who received conventional care in the original protocol and who re-
enrolled into the current protocol and who were treated with hPTH;
Cohort 3:  new subjects who initially enrolled into the current protocol. 
Subjects in cohort 1 will be analyzed separately from the other subjects; only safety analyses will 
be conducted on this cohort.  Subjects in cohorts 2 and 3 will be combined, and efficacy and 
safety analyses will be conducted on this group. However, the timing of the baseline biopsy 
relative to the on-treatment biopsy differs in cohorts 2 and 3.  For cohort 2 there was a much 
longer period of time between the baseline biopsy and their 1, 2, or 4 year on hPTH biopsy, in 
that the baseline period also include their entire period being on conventional care.  Whereas for 
cohort 3, baseline biopsies were taken immediately prior to beginning hPTH.  Because of this 
difference, all efficacy analyses will be repeated on subjects in cohort 3 alone. 
Safety Population: The Safety Population will consist of all enrolled subjects (all cohorts) who 
have started any study treatment including, but not limited to, conventional care. This population 
will be used for safety data summaries.
Bone Biopsy Population: The Bone Biopsy Population will consist of all subjects who have 
completed both their baseline and randomized 1, 2, or 4 year bone biopsies. This will include 
subjects from cohorts 2 and 3. 
Secondary Efficacy Population: This population consists of all subjects who received at least 
one dose of hPTH and had at least one post-baseline non-biopsy efficacy assessment. This will 
include subjects from cohorts 2 and 3.


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5.
STUDY PATIENTS
5.1
Disposition of Patients
Subject disposition will be summarized for the total set of enrolled (ie, consented) subjects by 
study cohort.  The subject disposition table will include:
x
Number of enrolled subjects,
x
Number of subjects in the safety, bone biopsy, and in the secondary efficacy populations
x
Number and percentage of subjects completing the study and the number of those terminating
early,  and
x
Number and percentage of subjects terminating early by reason for early termination.
For the presentation of the early terminations and reasons for early terminations, subjects will be 
counted under the last study visit completed prior to early termination.  
5.2
Protocol Deviations
For cohorts 2 and 3, protocol deviations reported on the current protocol will be summarized by 
deviation type in a table and subject listing (as previously provided to the DSMB).


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6.
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Subject demographics at baseline will be summarized descriptively for each analysis population
and cohort combination with appropriate descriptive statistics (number and percentages for 
categorical variables and mean, standard deviation, median, minimum and maximum for 
continuous variables). Demographic data will include: sex, ethnicity, race, age, weight, height, 
and body mass index (BMI).


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7.
EFFICACY EVALUATION
7.1
Handling of Dropouts or Missing Data
Missing data will not be initially imputed for the primary efficacy analyses. However, if the 
pattern of missing data in the primary efficacy analyses suggests the possibility of causing bias 
then as a secondary analysis, the primary analysis will be repeated using imputed values as 
described in section 7.4.3 below.  
7.2
Efficacy Analysis
7.2.1
Primary Study Endpoints
The primary endpoints are changes in static and dynamic bone histomorphometry after 1 year, 2 
years, and 4 years of hPTH therapy. These changes will be determined from antibiotic-labeled 
biopsies taken before and during hPTH therapy. The original protocol called for analyzing 7 bone 
markers of static and dynamic bone histomorphometry but the SAP has changed these to 8 bone 
markers of bone structure and bone remodeling. Analyses will be done on z-scores, when 
normative data are available. These are listed as follows:
7.2.1.1
Bone Structure
1.
Cn.BV/TV: cancellous bone volume
2.
Ct.Po.N: total number of cortical porosity per mm2
7.2.1.2
Cancellous Bone Remodeling
1.
Cn.BFR/BS: Cancellous bone formation rate
2.
Cn.MS/BS: Cancellous mineralizing surface (bone surface based)
7.2.1.3
Endocortical Bone Remodeling
1.
Ec.BFR/BS:  Endocortical bone formation rat.
2.
Ec.MS/BS: Endocortical mineralizing surface (bone surface based)
7.2.1.4
Intracortical Bone Remodeling
1.
Ic.BFR/BS: Intracortical bone formation rate
2.
Ic.MS/BS:  Intracortical mineralizing surface (bone surface based)


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7.2.2
Secondary Study Endpoints
7.2.2.1
Static and dynamic bone histomorphometry (After 1, 2, and 4 years of hPTH) in 
secondary bone biomarkers
Analyses relating to bone endpoints listed below will be done on z-scores, when 
normative data are available.
1.
Bone Structure
a.
Tb.Th:  Trabecular Thickness
b.
Tb.N:  Trabecular Number
c.
Tb.Sp:  Trabecular Separation
d.
Ct.Th:  Average Thickness of Inner and Outer Cortices
e.
Ct.Ar:  Total Area of Inner and Outer Cortices
f.
Ct.Po.Ar:  Total Area of Cortical Porosity
2.
Cancellous Bone Remodeling
a.
Cn.O.Th: Osteoid Thickness
b.
MAR: Bone Mineral Apposition Rate
c.
OS/BS: Osteoid Surface / Bone Surface
d.
ES/BS: Eroded Surface  / Bone Surface
e.
AjAR: Adjusted Apposition Rate
3.
Endocortical bone remodeling
a.
Ec.O.Th: Osteoid Thickness
b.
Ec.MAR: Bone Mineral Apposition Rate
c.
Ec.OS/BS: Osteoid Surface/Bone Surface
d.
ES/BS:  Eroded Surface  / Bone Surface


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e.
AjAR: Adjusted Apposition Rate
4.
Intracortical bone remodeling
a.
O.Th: Osteoid Thickness
b.
MAR: Bone Mineral Apposition Rate
c.
OS/BS: Osteoid Surface / Bone Surface
d.
ES/BS: Eroded Surface  / Bone Surface
e.
AjAR: Adjusted Apposition Rate
7.2.2.2
Changes in bone mineralization density (BMD) distribution will be assessed in bone 
biopsies by back-scattered electron imaging at 1, 2 and 4 years of hPTH therapy. The 
specific outcomes that will be measured include:
Analyses will be done on z-scores, when normative data are available.
1.
Spectral calcium-mean
2.
Calcium-peak
3.
Calcium-width
4.
Calcium low
5.
Calcium high
7.2.2.3
Non-biopsy outcomes are being measured every 6 months (annually for some 
outcomes) over the 5 years of hPTH therapy. Changes from baseline in the following 
outcomes will be assessed: 
1.
Biochemical markers of bone metabolism: osteocalcin, bone-specific alkaline
phosphatase, collagen cross-linked N-telopeptide.
2.
Serum and urine calcium; 1,25-OH2-Vitamin D
3.
Bone mineralization density assessed by DXA and quantitative CT  including both raw
and z-scores (based upon sex and age).  These will include measures at the following
anatomical sites
a.
AP Spine
b.
Lateral Spine


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c.
Femoral Neck
d.
Total Hip
e.
1/3 Radius
f.
Whole Body
The quantitative CT is limited to only the spine.
4.
Nephrocalcinosis and Nephrolithiasis by ultrasound and CT
5.
Fatigue Symptom Inventory
6.
6-Minute Walk Test
7.
SF-36 Health Survey
7.3
Tertiary Outcome Measures
7.3.1
Changes in blood chemistries
Blood parameters include serum albumin, calcium, phosphorus, magnesium, sodium, potassium, 
chloride, total CO2, creatinine glucose, and urea nitrogen.  
7.3.2
Changes in fibrobast growth factor 23
This was assessed via fibroblast growth factor 23 (FGF23) analysis of the blood.
7.3.3
Changes in renal mineral handling and PTH sensitivity 
Parameters for analysis include urine cAMP, creatinine, phosphorus, calcium, and pH. 
7.4
Analysis Methods
All study endpoints used in analyses will be summarized in tables.  Continuous endpoints will be 
summarized over time using n, mean ± se, median, min, max.  Endpoints requiring log-
transformation will also be summarized over time using geometric means with their 95% 
confidence limits. Ordinal endpoints will be summarized using medians, min, max, and their 10th
and 90th percentiles. Categorical endpoints will be summarized using number and percent in each 
category.


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All efficacy analyses related to the bone biopsies will be performed on the Bone Biopsy 
Population.  All efficacy analyses other than the bone biopsy related endpoints will be performed 
on the Secondary Efficacy Population.
For subjects who enter menopause during the study, any of their efficacy endpoints collected 
during or post-menopause will be excluded from the efficacy analyses, and will have such 
endpoints reported separately in the subject listings.  
Unless otherwise stated, all statistical inference will be based on an alpha level of 0.05 with 
adjustments for multiple comparisons when needed as described below. Analyses will be made 
using SAS (SAS Institute, Cary, North Carolina), version 9.4 or later. 
7.4.1
Primary Efficacy Analyses 
Separate primary analyses will be performed for each of the eight primary bone structure and 
bone remodeling biopsy endpoints listed in section 7.2.1. Since the study was terminated early 
and is thus under-powered, no corrections for multiplicity will be made in the analyses of the 8
primary efficacy endpoints.  For each of these primary bone biopsy endpoints, the primary 
analysis will test for differences with respect to the time of the biopsy (baseline, 1, 2, and 4 year).  
These endpoints will be analyzed using repeated measures mixed models with the bone biopsy
endpoint as the dependent variable, the baseline value of the bone biopsy endpoint and study 
cohort as covariates, biopsy time (baseline, 1 year, 2 year, and 4 year) as the repeated measure, 
and subject as the random variable.  The repeated measures will include a time-dependent 
covariate to adjust the baseline biopsy of Cohort 2 for the time delay between the baseline biopsy 
and the start of hPTH treatment.  This covariate will adjust Cohort 2 for any possible further 
progression of disease occurring between the baseline biopsy measures and the start of hPTH 
therapy. An indicator variable in the statistical model will set the effects of this time-dependent 
covariate to zero for Cohort 3 and for the post-baseline biopsies of Cohort 2.
Pairwise contrasts between the bone biopsy times will be performed within the repeated measures 
analyses to compare the effects of the biopsy times on the bone biopsy endpoints. Because the 
sample size for 2-year and 4-year biopsies are reduced in size due to withdrawal and the early 
termination of the study, the 2-, and 4-year biopsies may be combined into one group provided 
their effects are qualitatively similar (i.e. the estimates of their effects are in the same direction).  
If the 2- and 4-year biopsies are qualitatively different then the 4-year biopsies may be dropped 
from the analysis due to its small sample size.  The post hoc pairwise comparisons among the 


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biopsy time-points will be corrected for multiple comparisons using Fisher’s protected LSD with 
Bonferroni corrections when the overall effect of biopsy year is not statistically significant.
Residual analysis will be used to confirm that model assumptions are reasonable.  Log-
transformations of the bone biopsy endpoints will be made if indicated by the residual analysis.  
The repeated measures will be fit using both a compound symmetry and an unstructured 
covariance structure.  The better covariance structure will be selected as the model with the better 
Schwarz’s Bayesian criterion. If the residual analyses of the statistical models indicate a failure 
to meet the assumptions of the repeated measures statistical models then other methods of 
statistical analysis including nonparametric analysis may be considered. 
7.4.2
Secondary Efficacy Analyses 
7.4.2.1
Covariate adjustments for dose on the primary efficacy analysis models of the bone 
biopsy endpoints
The bone biopsy repeated measures analyses described in the primary analyses will be explored 
further by repeating the same analysis but with hPTH dose as an additional covariate.  Four 
measures of dose will be tested as covariates: 1) average dose over the last 6 months prior to the 
bone biopsy or weaning whichever comes earlier; 2) average dose per kg body weight over the 
last 6 months prior to the bone biopsy or weaning whichever comes earlier; 3) total daily dose 
across the whole study up to the time of the bone biopsy or weaning whichever comes earlier; 
and, 4) total dose per kg of body weight across the whole study up to the time of the bone biopsy 
or weaning whichever comes earlier .  The effects of these dose measures on the bone biopsy 
results will be modeled separately fitting both linear and quadratic (curvilinear) effects for the 
dose variable. The best covariate models will be selected based upon examination of the 
residuals and comparison of the Schwarz-Bayesian criterion.  
The relationships between dose and bone biopsy endpoint will be graphically illustrated using 
scatterplots of the bone biopsy endpoint over dose with appropriate regression lines.  
7.4.2.2
Sensitivity analyses of female menopause status in the primary bone biopsy efficacy 
models
Sensitivity analyses will be performed to test the effects menopause status in females on our best 
primary efficacy bone biopsy repeated measures models (with or without dose covariates, 
sections 7.4.1 and 7.4.2.1).  Menopause status will be tested as a covariate in the statistical 
models (excluding males). The covariate for menopausal status will be parameterized into a 
categorical variable with 2 levels:  1) pre-menopausal female; and 2) menopausal or post-


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menopausal female.  If the data is rich enough, further exploratory analyses may test for 
interactions between dose, and menopausal status. Best models will be selected based upon 
residual analysis and the Schwarz-Bayesian criterion.  Results will be summarized in tables.
7.4.2.3
Changes in bone mineralization density based on back-scattered electron imaging of 
bone-biopsies
Parameters derived from the back-scattered electron imaging of the bone biopsies include the 
spectral calcium mean, peak, width, low, and high. These spectral calcium parameters will be 
analyzed separately using repeated measures mixed models with the spectral calcium parameter
as the dependent variable, the baseline value of the biopsy endpoint and study cohort as
covariates, biopsy time (baseline, 1 year, 2 year, and 4 year) as the repeated measure, and subject 
as the random variable.  Because there are only a few subjects with the 4 year biopsy, the 2 and 4 
year biopsies may be collapsed into one biopsy group for analysis purposes if the 2 and 4 year 
biopsies appear to have similar effect sizes and variances.  If the 2- and 4-year biopsies are 
qualitatively different  then the 4-year biopsy endpoints may be dropped from the analysis due to 
their small sample sizes. Pairwise contrasts will be performed within the repeated measures 
analyses to compare the effects of the biopsy times on the bone biopsy endpoints. 
Since these spectral calcium parameters are secondary endpoints, these analyses are considered 
more exploratory and thus no adjustments will be made for performing multiple secondary 
analyses. However, post hoc pairwise comparisons within each repeated measures analysis will 
be controlled for multiple comparisons using Fisher’s protected LSD followed by Bonferroni 
correction if the overall effect is not significant.
Results will be summarized in a table.  The effects of hPTH treatment on the spectral calcium 
endpoint will be illustrated in figures of the mean ± se (or geometric means with 95% confidence 
limits) over biopsy time. 
7.4.2.4
Repeated measures analyses of the non-biopsy secondary endpoints
The secondary non-biopsy secondary endpoints are listed in section 7.2.2.
Unlike the biopsy endpoints, the secondary non-biopsy secondary endpoints had measurements at 
baseline and then every 6 months over the 5 years of the study as compared to biopsies at 
baseline, 1, 2, and 4 years of hPTH treatment.  As a complication, subjects were on hPTH therapy 
for various lengths of time due to study withdrawal and early study termination. Thus, the effects 
of study month are not the same for each subject with some subjects on hPTH therapy and some 


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Protocol No. 07-D-0016
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subjects off hPTH therapy for the later study months.  Thus, the 6-month time-points will be 
reduced to the following experimental time-points: baseline visit, 6-month study visit, end of 
hPTH therapy, and post-hPTH follow-up visit.
The effect of hPTH therapy over the experimental time-points (baseline, 6-month study visit, last 
hPTH treatment, and post-hPTH follow-up) on each of the non-biopsy endpoint parameters will 
be analyzed using repeated measures mixed models with the non-biopsy endpoint as the 
dependent variable, the baseline value of the non-biopsy endpoint, and study cohort as covariates, 
the experimental time-point as the repeated measure, and subject as the random factor.  If dose is 
found to improve model fits in the bone-biopsy repeated measures analyses (section 7.4.2.1) then 
the effect of dose will be added as a covariate to these secondary repeated measures. Pairwise 
post hoc comparisons will be made to test for endpoints differences among the experimental time-
points (baseline, 6-month study visit, last hPTH treatment, and post-hPTH follow-up). The 
significance of these post hoc pairwise comparisons will be corrected for multiple comparisons 
using Fisher’s protected LSD. When the repeated measures overall effects of study time-point 
are not significant, Bonferroni corrections will be used to adjust the pairwise contrasts for 
muiltiplicity. 
Residual analysis will be used to confirm that repeated measures model assumptions are 
reasonable.  Log-transformations of the bone biopsy endpoints will be made if indicated by the 
residual analysis.   The repeated measures will be fit using both a compound symmetry and an 
unstructured covariance structure.  The better covariance structure will be selected as the model 
with the better Schwarz- Bayesian criterion.  
7.4.2.5
Summary of the effects of hPTH weaning on serum calcium, phosphorus, calcitriol, 
and biomarkers of bone turnover.
The effects of weaning subjects off hPTH will be summarized descriptively by the study PI.  
Mixed models repeated measures analysis will test treatment effects on 10 outcome measures: 
serum calcium, serum phosphorus, 3 bone turnover markers (Osteocalcin, n-Telopeptide, and 
Alkaline Phosphatase), and 5 DEXA Bone Mass Density (BMD) parameters.  The DEXA bone 
mass density measures included:  AP spine BMD, femoral neck BMD, total hip BMD, Forearm 
BMD, and whole body BMD. Treatment effects will be summarized at three study time-points:  
Baseline (immediately at start of hPTH treatment), Treatment (immediately prior to Weaning, i.e. 
end of hPTH treatment), and Follow-up. The repeated measures analyses will be performed using
each of these 10 outcome measures as the dependent variables, with random effects for subject, 


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and repeated fixed effects for 3 study time-points within a subject   These outcome measures will 
be log-transformed if necessary to normalize the data. Two covariance structures will be tested 
(compound symmetry and unstructured) and the covariance structure with the smallest Bayesian 
Information Criterion (BIC) and the best residual distributional properties will be used.  Pairwise 
post hoc contrasts will be made to compare the effects of treatment at the study time-points.  
These post hoc pairwise contrasts will be corrected for multiple comparisons using Fisher’s 
protected LSD will Bonferroni corrections when the overall effect of time is not significant. 
Rho will provide figures with panel columns for the subject and the panel rows for the time 
course (baseline, during hPTH, through the start of weaning to the post-hPTH follow-up) of oral 
elemental calcium and calcitriol dosing, plasma calcium, and PTH dose.
7.4.2.6
Summary of hPTH therapy on nephrocalcinosis and nephrolithiasis by ultra sound 
and CT
The rate of new, stable, and progressing nephrocalcinosis and nephrolithiasis (NC/NL) in study 
subjects will be summarized.
7.4.3
Other Efficacy Analyses 
If there is a high study withdrawal rate before the second biopsy for reasons other than the final 
termination of the study then patterns associated with subject withdrawal will be analyzed with 
respect the primary bone biopsy endpoints. If the patterns associated with early withdrawal 
suggest a possible source of bias, then a sensitivity analysis on the primary efficacy analyses 
using multiple imputation (Proc MI in SAS) will be employed.
The tertiary outcomes include changes in blood chemistries, FGF23, renal mineral handling, and 
PTH sensitivity will be analyzed using repeated measures if the outcome is continuous or using 
contingency tables for categorical outcomes.  Results will be summarized in tables.  Figures will 
be provided upon request.


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8.
SAFETY EVALUATION
Safety evaluation will include all tables and listings previously provided for the DSMB.  
Additional safety tables and listing will be provided if requested by the study PI. 


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9.
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL
The study was discontinued early, due to pharmacy issues.  Upon termination of new enrollment 
in June of 2015, subjects began to be slowly weaned off of hPTH.  Of the 32 planned, newly 
enrolled subjects, only 19 were actually enrolled and treated and of these, 8 subjects provided 
their on-treatment biopsy. This early termination provides less power to detect significant 
differences in endpoints. We will evaluate the possibility of combining the 2- and 4- year biopsy 
groups to address this issue (see section 7.4.1 for details).
The primary bone biopsy endpoints have changed.  The original primary endpoints included: 1) 
mineralized perimeter; 2) bone formation rate; 3) cortical width; 4) cortical area; 5) osteoid width; 
6) osteoid perimeter; and 7) mineral apposition rate.  These primary bone biopsy endpoints have
been replaced with the eight primary endpoints listed in section 7.2.1. In the analysis of the pilot 
study of the first 5 patients as well as other relevant pilot studies, we learned that these are the 
more informative indices. 
The primary and secondary analyses will be performed using repeated measures mixed models 
rather than the paired t-tests, ANOVA, and ANCOVA analyses as stated in the protocol.
Although the protocol specifies imputation analyses for all secondary endpoints collected every 6
months over the 5-year study period, for purposes of efficiency the sensitivity analyses using 
multiple imputation (Proc MI in SAS) of missing values will be initially limited to the primary 
efficacy bone biopsy endpoints. After reviewing patterns of missing-ness in the secondary 
endpoints, additional sensitivity analyses involving multiple imputations may be performed at the 
request of the PI. 


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Protocol No. 07-D-0016
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10. LIST OF PLANNED TABLES
Subject listings associated with the tables below will be provided. Experimental time refers to the 
baseline, last hPTH treatment, and post-hPTH follow-up visits. Additional tables (eg, those based 
on the results of sensitivity analysis) will be provided.  Other displays, as requested by the PI may 
be provided as well. 
Table Type
Table
Disposition
Summary of Subject Disposition
Demographics
Summary of Study Enrollment by Demographic Characteristics
hPTH Therapy
Summary of the Duration of hPTH Therapy
Primary Efficacy
Summary Statistics of Primary Bone Biopsy Endpoints by Biopsy Year.
(Separate tables for Cohorts 2, 3, and Cohort 2 combined with Cohort 3) 
Repeated Measures Analysis of Primary Efficacy Analysis
(Separate tables for Cohorts 2, 3, and Cohort 2 combined with Cohort 3) 
Secondary 
Efficacy
Summary of Bone Mineralization Density Assessed by Back-Scattered 
Electron Imaging by Years of hPTH therapy
Summary of Biochemical Markers of Bone Metabolism by Experimental 
Time Including the Statistical Significance of Changes.
Summary of Blood and Urine Chemistries by Experimental Time Including 
the Statistical Significance of Changes.
Summary of Bone Mineralization Density Assessed by DXA and 
Quantitative CT by Experimental Time Including the Statistical Significance 
of Changes.
Summary of Nephrocalcinosis and Nephrolithiasis by Time on Study Drug
Summary of Fatigue Symptom Inventory and 6-Minute Walk Test by 
Experimental Time Including the Statistical Significance of Changes.
Summary of SF-36 Health Survey by Experimental Time Including the 
Statistical Significance of Changes.
Adverse Events 
(as provided to 
DSMB)
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34
Summary of Adverse Events Occurring on or after hPTH 1-34
Summary of Adverse Events Occurring While on Conventional Care 
Summary of Adverse Events for Subjects on Conventional Care 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Current PI 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Prior to Current PI 
Summary of Adverse Events Occurring While on Conventional Care: Current 
PI 
Summary of Adverse Events Occurring While on Conventional Care: Prior to 
Current PI 


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Protocol No. 07-D-0016
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Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34; Related (Unlikely, Possible, Probable, or 
Definite) to hPTH 1-34
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34
Summary of Adverse Events Occurring on or after hPTH 1-34
Summary of Adverse Events Occurring While on Conventional Care 
Summary of Adverse Events for Subjects on Conventional Care 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Current PI 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Prior to Current PI 
Summary of Adverse Events Occurring While on Conventional Care: Current 
PI 
Summary of Adverse Events Occurring While on Conventional Care: Prior to 
Current PI 
Summary of Adverse Events Occurring While on Conventional Care: Events 
During the Reporting Period 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Current PI 
Summary of Adverse Events Occurring While on hPTH 1-34 or After 
Withdrawal from hPTH 1-34: Prior to Current PI 
Summary of Adverse Events Occurring While on Conventional Care: Current 
PI 
Summary of Adverse Events Occurring While on Conventional Care: Prior to 
Current PI 
Summary of Exposure to hPTH at Time of First On-Treatment Event within a 
6XEMHFWDQG62&3UHIHUUHG7HUP,QFOXGHV2QO\(YHQWV2FFXUULQJIRU
Subjects Within a Category
Protocol 
Deviations
(as provided to 
DSMB)
Summary of Protocol Deviations

Prot_ICF_001.pdf: 
PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 1 of 55 
 
Protocol Title:  Effects of PTH Replacement on Bone in Hypoparathyroidism 
 
Abbreviated Title:  PTH on Bone in Hypoparathyroidism 
Protocol Number: 07-D-0016, Version 17.0 
Date of this Submission: September 9, 2015 
 
Principal Investigator 
Name, Degree 
Rachel I. Gafni, MD 
Branch/Institute 
CSDB,NIDCR 
Bldg/Rm 
30/228 
Phone 
 301-594-9924 
E-mail 
gafnir@mail.nih.gov  
 
 
Associate Investigators 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
Beth Brillante, RN, MBA 
NIDCR 
10/9C403 
301-451-2260 
bbrillante@mail.cc.nih.gov  
Lori Guthrie, RN 
NIDCR 
10/8N118A 301-594-0844 
guthriel@mail.nih.gov 
James Reynolds, MD 
CC 
10/1C461 
301-496-5675 
jreynolds@mail.cc.nih.gov  
Alison Boyce, MD 
NIDCR 
30/228 
301-443-2700 
alison.boyce@nih.gov 
Michael T. Collins, MD 
NIDCR 
30/228 
301-496-4913 
Mc247k@nih.gov 
Laura L. Tosi, MD 
NHGRI 
10/3C710 
301-453-2832 
ltosi@childrensnational.org 
Andrea Burke, MD, DMD 
NIDCR 
30/228 
301-443-2704 
Andrea.burke@nih.gov 
Mary Scott Ramnitz, MD 
NICHD 
30/228 
301-408-6988 
Maryscott.ramnitz@nih.gov 
 
Non-NIH Collaborators 
Name, Degree 
Institution/Location 
E-mail 
Hua Zhou, MD 
Helen Hayes Hospital 
zhouh@helenhayeshosp.org 
David Dempster, PhD 
Helen Hayes Hospital 
dempster@helenhayeshosp.org 
Klaus Klaushofer, MD 
Ludwig Boltzmann Institute of Osteology, 
Vienna, Austria 
Klaus.Klaushofer@osteologie.at   
 
Paul Roschger, PhD 
Ludwig Boltzmann Institute of Osteology, 
Vienna, Austria 
paul.roschger@osteologie.at      
Craig Langman, MD 
Northwestern University, CMH 
c-langman@northwestern.edu  
 
Research Contact  
Lori Guthrie, RN 
 
CSDB/NIDCR 
10/8N11 
301-594-0844 
guthriel@mail.nih.gov 
 
Medical Advisory Investigator 
Name, Degree 
Branch/Institute 
Bldg/Rm 
Phone 
E-mail 
 
Total requested accrual: 
Subjects – maximum accrual 69  (36 new subjects to start PTH, up to 10 screened but not started 
on PTH, 23 previously enrolled)   
 
 Volunteers (0)  
  
 
Project Uses Ionizing Radiation:    
o No  x Yes  
 
 
 
 
 
o Medically-indicated only 
 
 
 
 
 
o Research-related only 
 
 
 
 
 
x Both 
 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 2 of 55 
 
IND/IDE 
 
 
 
o No   
xYes  
 
 
Drug/Device/#: PTH 1-34/#102,394 
 
 
Sponsor: 
 
Rachel I. Gafni, MD 
 
Durable Power of Attorney:  
 
x No   
o Yes  
Multi-institutional Project: 
 
o No   
 x Yes  
 
 
 
 
 
 
 
Institution: Helen Hayes and Ludwig Boltzmann FWA # 00005897 
 
Date of IRB approval: __February 14, 2012 (Helen Hayes Hospital)_________  
 
Data and Safety Monitoring Board: 
 o No x Yes   
 
Technology Transfer Agreement: 
o No  x Yes  
Agreement type and number:  
 
MTA 2008-916, 2008-917    Expiration Date_none 
David Dempster (via Helen Hayes Hospital)  
Klaus Klaushofer (via Ludwig Boltzmann Institute of Osteology)  
 
Confidential Disclosure Agreement:   
x No 
o Yes 
 
Samples are being stored: 
 
o No  x Yes 
Flesch-Kincaid reading level of consent form: 9.1 (7.9 excluding the term “hypoparathyroidism”) 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 3 of 55 
 
Précis 
Objectives 
The primary objective of this study is to evaluate the skeletal effects of hormone replacement therapy 
with HPTH in hypoparathyroidism.  
Study Population 
This study will enroll up to 69 subjects with physician-diagnosed hypoparathyroidism. 
  
Design 
This study will treat hypoparathyroid individuals with synthetic human PTH 1-34 (HPTH) for up to 5 
years, periodically assessing skeletal changes through biochemical markers and iliac-crest bone biopsies, 
which will allow for ultrastructural, cellular, and molecular analyses.  
With respect to HPTH treatment, this study is a single group, within-subjects, repeated measures 
treatment trial. With respect to all bone biopsy analyses, the design is a parallel group design with each 
subject allocated to one of the 3 biopsy follow-up times:  1, 2 or 4 years after initiation of HPTH therapy.  
Post-baseline biopsy timing will be randomly assigned (1:1.2:1.4, respectively) to each subject, stratified 
by gender and by menopausal status, when relevant.  Changes from baseline (time 0) to 1, 2 and 4-years 
will be compared.  Subjects who were on conventional therapy in the former version of the protocol will 
also be randomized into the new study design. In contrast to new subjects, whose biopsy is performed at 
the end of the conventional care run-in period, the pre-conventional care biopsy will be used as the 
baseline for the those subjects entering the new design after having been on conventional care in the older 
protocol. Because it is not known with certainty what effects duration of time on conventional therapy 
will have on biopsy results, randomization will also be stratified on status of prior study participation. The 
subjects who were on HPTH therapy at the time of the protocol redesign are followed as a separate group 
under this protocol.  
Outcome Measures 
Primary: 
Changes in static and dynamic bone histomorphometry after 1 year, 2 years, and 4 years of HPTH 
therapy. Primary outcome measurements include: 
x Mineralized perimeter 
x Bone formation rate 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 4 of 55 
 
x Cortical width 
x Cortical area 
x Osteoid width 
x Osteoid perimeter 
x Mineral apposition rate 
Secondary: 
1. 
Changes in bone mineralization density distribution at 1, 2 and 4 years of HPTH therapy. The 
specific outcomes that will be measured include: 
x Spectral calcium-mean 
x Calcium-peak 
x Calcium-width 
2. 
Changes from baseline will be assessed in the following outcomes:  
x Biochemical markers of bone metabolism: osteocalcin, bone-specific alkaline 
phosphatase, collagen cross-linked N-telopeptide.  
x Serum and urine calcium; 1,25-OH2-Vitamin D 
x Bone density assessed by DXA and quantitative CT 
x Nephrocalcinosis by ultrasound and CT 
x Fatigue Symptom Inventory 
x 6-Minute Walk Test 
x SF-36 Health Survey 
Tertiary: 
Changes in blood chemistries and FGF23, renal mineral handling, and PTH sensitivity with the initiation 
of HPTH, which include:   
x Serum albumin, calcium, phosphorus, magnesium, sodium, potassium, chloride, Total 
CO2, creatinine, glucose, urea nitrogen, and FGF23 
x Urine cAMP, creatinine, phosphorus, calcium, and pH 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
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Page 5 of 55 
 
 
Table of Contents 
PRÉCIS ........................................................................................................................................... 3 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF ABBREVIATIONS ......................................................................................................... 8 
1 
INTRODUCTION ............................................................................................................... 10 
2 
STUDY OBJECTIVES ........................................................................................................ 13 
2.1 
Primary Objective ............................................................................................................ 13 
2.2 
Secondary Objectives ...................................................................................................... 13 
2.3 
Tertiary Objective ............................................................................................................ 13 
3 
SUBJECTS .......................................................................................................................... 13 
3.1 
Description of Study Populations .................................................................................... 13 
3.2 
Inclusion Criteria ............................................................................................................. 14 
3.3 
Exclusion Criteria ............................................................................................................ 14 
4 
STUDY DESIGN AND METHODS................................................................................... 15 
4.1 
Study Overview ............................................................................................................... 15 
4.2 
Recruitment ..................................................................................................................... 16 
4.3 
Screening ......................................................................................................................... 16 
4.3.1 
Pre-Screening ............................................................................................................ 16 
4.3.2 
Inpatient Screening Visit ........................................................................................... 17 
4.4 
Study Design ................................................................................................................... 18 
4.5 
Study Procedures ............................................................................................................. 19 
4.5.1 
Conventional Therapy Prior to Start of HPTH .......................................................... 19 
4.5.2 
Inpatient Baseline Visit and Start of HPTH Therapy ................................................ 19 
4.5.3 
Follow-up Visits During HPTH Therapy .................................................................. 21 
4.5.4 
Outpatient Blood and Urine Collections ................................................................... 23 
4.5.5 
Monitoring of Calcium-Citrate Ratio and Concomitant Potassium Citrate .............. 24 
4.5.6 
Bone Biopsy Procedures ........................................................................................... 24 
4.6 
End of Participation ......................................................................................................... 24 
4.6.1 
Post HPTH Therapy Stabilization and Follow-up ..................................................... 24 
4.7 
Communication with Referring Physicians ..................................................................... 26 
5 
STORAGE OF DATA AND SAMPLES ............................................................................ 26 
5.1 
Data.................................................................................................................................. 26 
5.2 
Samples............................................................................................................................ 26 
5.2.1 
Samples and Data Management after Completion of the Protocol ........................... 27 
5.2.2 
Research Collaborations Involving Stored Specimens or Data ................................. 27 
6 
ADDITIONAL CONSIDERATIONS ................................................................................. 27 
6.1 
Research with Investigational Drugs or Devices ............................................................. 27 
6.1.1 
Synthetic Human Parathyroid Hormone (HPTH) ..................................................... 27 
6.1.2 
Pharmacokinetics ....................................................................................................... 28 
6.1.3 
Pharmacodynamics .................................................................................................... 28 
6.1.4 
Formulation and Preparation ..................................................................................... 28 
6.1.5 
Storage, Stability, and Handling ................................................................................ 28 
6.1.6 
Packaging and Labeling ............................................................................................ 29 


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6.1.7 
Receipt, Dispensation, and Return of Clinical Supplies ........................................... 29 
6.1.8 
Investigational Product Administration ..................................................................... 30 
6.2 
Gene Therapy .................................................................................................................. 30 
7 
RISKS / DISCOMFORTS ................................................................................................... 30 
7.1 
Assessment/Procedures with no Risks or Noteworthy Discomfort ................................. 30 
7.2 
6-Minute Walk Test ......................................................................................................... 30 
7.3 
Blood Draws .................................................................................................................... 30 
7.4 
72BDNA Testing ................................................................................................................... 31 
7.5 
Urine Collection .............................................................................................................. 31 
7.6 
Renal Ultrasound ............................................................................................................. 31 
7.7 
Radiation.......................................................................................................................... 31 
7.8 
Tetracycline Antibiotics for Bone Biopsy Labeling ........................................................ 31 
7.9 
Trans-iliac Crest Bone Biopsy......................................................................................... 32 
7.10 HPTH ............................................................................................................................... 32 
7.10.1 FDA-Approval ........................................................................................................... 32 
7.10.2 Carcinogenesis, Mutagenesis, and Reproductive Toxicology ................................... 32 
7.10.3 Drug Interactions ....................................................................................................... 33 
7.10.4 Adverse Events .......................................................................................................... 33 
8 
SUBJECT SAFETY MONITORING .................................................................................. 34 
9 
OUTCOME MEASURES ................................................................................................... 35 
9.1 
Primary Outcome Measures ............................................................................................ 35 
9.2 
Secondary Outcome Measures ........................................................................................ 36 
9.3 
Tertiary Outcome Measures ............................................................................................ 37 
10 
STATISTICAL ANALYSIS ............................................................................................... 37 
10.1 Analysis of Data/Study Outcomes................................................................................... 37 
10.2 Power Analysis ................................................................................................................ 39 
10.3 Randomization and Stratification .................................................................................... 40 
11 
HUMAN SUBJECTS PROTECTION ................................................................................ 40 
11.1 Subject Selection ............................................................................................................. 40 
11.2 Justification for Exclusion of Children ............................................................................ 41 
11.3 Justification for Exclusion of Other Vulnerable Subjects ............................................... 41 
11.4 Justification of Sensitive Procedures ............................................................................... 41 
11.5 Safeguards for Vulnerable Populations ........................................................................... 41 
11.6 Qualifications of Investigators ........................................................................................ 41 
11.7 Qualifications of Non-NIH Collaborators ....................................................................... 42 
12 
ANTICIPATED BENEFIT .................................................................................................. 42 
13 
CLASSIFICATION OF RISK ............................................................................................. 43 
13.1 Adults .............................................................................................................................. 43 
13.2 Overall Risk and Benefit Consideration .......................................................................... 43 
14 
CONSENT DOCUMENTS AND PROCESS ..................................................................... 43 
14.1 Designation of Those Obtaining Consent........................................................................ 43 
14.2 Consent Procedures ......................................................................................................... 43 
14.3 Consent Documents ......................................................................................................... 43 
15 
DATA AND SAFETY MONITORING .............................................................................. 44 
15.1 Data and Safety Monitor ................................................................................................. 44 


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15.2 4BData and Safety Monitoring Plan .................................................................................... 44 
15.3 Criteria for Stopping the Study or Suspending Enrollment or Procedures ..................... 45 
15.4 Data and Safety Monitoring Committee Oversight ......................................................... 46 
16 
QUALITY ASSURANCE ................................................................................................... 47 
16.1 Quality Assurance Monitor ............................................................................................. 47 
16.2 Quality Assurance Plan ................................................................................................... 47 
17 
UNANTICIPATED PROBLEM,  ADVERSE EVENT,  AND PROTOCOL DEVIATION 
REPORTING ....................................................................................................................... 48 
17.1 Pregnancy Reporting and Follow-Up .............................................................................. 49 
18 
ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES ................ 49 
19 
CONFIDENTIALITY.......................................................................................................... 49 
19.1 Research Data and Investigator Medical Records ........................................................... 49 
19.2 Stored Samples ................................................................................................................ 50 
19.3 Special Precautions .......................................................................................................... 50 
20 
CONFLICT OF INTEREST / TECHNOLOGY TRANSFER ............................................ 50 
20.1 Distribution of NIH Guidelines ....................................................................................... 50 
20.2 Conflict of Interest ........................................................................................................... 50 
20.3 Role of a Commercial Company or Sponsor ................................................................... 50 
21 
TECHONOLOGY TRANSFER .......................................................................................... 50 
22 
RESEARCH AND TRAVEL COMPENSATION .............................................................. 51 
23 
REFERENCES .................................................................................................................... 52 
24 
APPENDICES ..................................................................................................................... 55 
24.1 Adverse Event and Unanticipated Problem, and Protocol Deviation Definitions, 
Characteristics and Additional Reporting Details .......................................................... 55 
24.2 Pre-Screening Questionnaire and Eligibility Checklist ................................................... 55 
24.3 Study Schema .................................................................................................................. 55 
24.4 Schedule of Events .......................................................................................................... 55 
24.5 Calcium Questionnaire .................................................................................................... 55 
24.6 DNA Consent Documents ............................................................................................... 55 
24.7 SF-36 Survey ................................................................................................................... 55 
24.8 Fatigue Symptom Inventory ............................................................................................ 55 
24.9 6-Minute Walk Test ......................................................................................................... 55 
24.10 Dosing Algorithm ............................................................................................................ 55 
24.11 Discharge Instructions ..................................................................................................... 55 
24.12 Bone Labeling Instructions.............................................................................................. 55 
24.13 Forteo Package Insert ...................................................................................................... 55 
24.14 Study Blood Draw Amounts ........................................................................................... 55 
25 
CONSENT FORMS............................................................................................................. 55 


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List of Abbreviations 
 
AE 
Adverse Event 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
ANCOVA 
Analysis of covariance 
AST 
Aspartate aminotransferase 
BMD 
Bone mineral density 
CaSR 
Calcium-sensing Receptor 
CBC 
Complete Blood Count 
CRF 
Case Report Form 
CT 
Computed Tomography  
DCC 
Data Coordinating Center 
DNA 
Deoxyribonucleic Acid 
DSMC 
Data and Safety Monitoring Committee 
DXA 
Dual-energy X-ray Absorptiometry 
eCRF 
Electronic Case Report Form 
FDA 
Food and Drug Administration 
HPTH 
Synthetic Human PTH 1-34 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
MCV 
Mean Corpuscular Volume 
NIDCR 
National Institute of Dental and Craniofacial Research 
NIH 
National Institutes of Health 
PDS 
Pharmaceutical Development Service 
PRPL 
Patient Recruitment and Public Liaison 
PTH 
Parathyroid Hormone 
rhPTH 
Recombinant human PTH 1-34 
RBC 
Red Blood Cells 
RDW 
Red Cell Distribution Width 
RSC 
Radiation Safety Committee 
SAE 
Serious Adverse Event 
UP 
Unanticipated Problem 


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WBC 
White Blood Cells 


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1 
INTRODUCTION  
1 
Parathyroid hormone (PTH) is an 84-amino acid peptide produced by the parathyroid glands; its primary 
2 
function is the maintenance of serum calcium levels by enhancing calcium release from the bone, 
3 
increasing calcium reabsorption by the kidney, and stimulating the formation of 1,25-OH2-Vitamin D, 
4 
which allows for increased intestinal calcium absorption. Hypoparathyroidism is a rare condition caused 
5 
by inadequate production or secretion of PTH. It may be due to a variety of genetic disorders, 
6 
autoimmune conditions and infiltrative diseases, or as a result of parathyroid gland injury or removal 
7 
during neck surgery. PTH deficiency leads to hypocalcemia, hyperphosphatemia, and, frequently, 
8 
hypercalciuria. The hypercalciuria can be particularly severe in patients with hypoparathyroidism due to 
9 
activating mutations in the calcium-sensing receptor; their altered responsiveness to ambient calcium 
10 
levels leads to urinary calcium wasting, even in the face of hypocalcemia. The manifestations of 
11 
hypocalcemia can be significant, including neuromuscular irritability causing tetany, cramping, 
12 
carpopedal spasms, and seizures. The only readily available and FDA-approved treatments are vitamin D 
13 
analogs such as calcitriol (1,25-OH2 Vitamin D) given in conjunction with calcium supplementation. 
14 
Calcitriol increases intestinal calcium absorption, leading to increased serum calcium levels, however it 
15 
does not correct the impaired renal calcium reabsorption that is typical of this disorder. Thus, while 
16 
conventional therapy may normalize serum calcium levels, management is often complicated by further 
17 
increases in urine calcium excretion. Chronic hypercalciuria may lead to nephrocalcinosis, renal 
18 
insufficiency or failure.1  
19 
Hypoparathyroidism is one of the few remaining hormone deficiencies for which hormone replacement 
20 
therapy is not approved. Replacement therapy using synthetic human parathyroid hormone 1-34 (HPTH) 
21 
in hypoparathyroidism has been studied in several clinical trials at the NIH. The initial crossover pilot 
22 
study of 10 subjects demonstrated that HPTH maintained both serum and urinary calcium in the normal 
23 
range over a 24-hour period when given as a single daily subcutaneous injection for 10 weeks.2 HPTH 
24 
resulted in a lower urinary calcium level than calcitriol for a given level of serum calcium. Subsequently, 
25 
results of a randomized controlled-dose study showed that twice-daily, compared to once daily, HPTH 
26 
given for 14 weeks provides effective short-term treatment for hypoparathyroidism with a markedly 
27 
reduced total daily dose, an apparent reduction in bone turnover, and a decreased incidence of bone pain 
28 
compared to a once-daily regimen. Twice daily HPTH produced higher levels of serum calcium, with 
29 
fewer fluctuations into the hypocalcemic range. Markers of bone turnover were elevated above the normal 
30 
range in response to both treatment regimens, however, twice daily produced significantly lower serum 
31 
marker levels suggesting that this dose regimen increased bone turnover to a lesser extent than once daily 
32 
HPTH.3 A similar study in children also showed better metabolic control with twice daily HPTH versus a 
33 


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single daily injection, however, there were no significant differences in bone markers between the 2 
34 
groups.4 In a long-term study, 27 adults with hypoparathyroidism were randomized to either calcitriol or 
35 
HPTH. The findings demonstrated that twice-daily HPTH administration maintains serum calcium in the 
36 
low normal or just below the normal range over a 3-year period; there were no statistically significant 
37 
difference in urine and serum calcium between the two groups. In the HPTH treated group, however, 
38 
markers of bone turnover (osteocalcin, alkaline phosphatase) were significantly elevated during the 3-year 
39 
study, at levels at least 2-fold greater than normal. Despite this increase in bone turnover, there was no 
40 
change in the bone mineral density (BMD) as measured with dual energy x-ray absorptiometry (DXA). 
41 
This contrasts with the calcitriol-treated group that experienced a rise in spinal bone mineral density over 
42 
time with no rise in bone markers.5 
43 
PTH deficiency is associated with decreased skeletal turnover. Adults with chronic hypoparathyroidism 
44 
develop hypermineralized, dense, bones that are abnormal in their geometric, histomorphometric, and 
45 
microarchitectural features, presumably due to chronic lack of bone turnover.6-8 Cortical width and 
46 
cancellous bone volume are increased, while dynamic indices of bone turnover such as bone formation 
47 
rate and mineral apposition rate are decreased.8 The cellular mechanisms underlying the evolution and 
48 
maintenance of the high bone mass in hypoparathyroidism have not been well explored. Remodeling 
49 
activities of bone cells (osteoclasts and osteoblasts) involve sequential breakdown of old bone and 
50 
formation of newly formed bone matrix. Normal bone remodeling involves the excavation of microscopic 
51 
areas of bone followed by the production of new bone to fill in these areas. Patients with 
52 
hypoparathyroidism have decreased remodeling activity with low bone turnover8 that leads to the 
53 
accumulation of bone that, under normal circumstances, would be replaced by newly formed bone matrix. 
54 
With replacement PTH therapy, the rise in bone turnover as evidenced by the rise in bone markers should 
55 
restore this physiologic state. The concern, however, is that in the 3-year NIH study,5 these biochemical 
56 
markers remain above the normal range, suggesting a chronically high bone turnover state. Recently, NIH 
57 
reported a case of a 20 year-old hypoparathyroid woman with a calcium sensing receptor (CaSR) 
58 
mutation treated with HPTH for 14 years; HPTH treatment did not ameliorate her hypercalciuria nor did it 
59 
prevent the development of nephrocalcinosis and bone biopsies revealed dramatic increases in cancellous 
60 
bone volume.9 However, her young age at the time of PTH initiation makes these finding not 
61 
generalizable to adults with hypoparathyroidism. An interim analysis of 5 subjects in this particular 
62 
protocol  study has demonstrated that, after 1 year of PTH therapy, bone volume and bone remodeling as 
63 
assessed by bone biopsy and biochemical markers are markedly increased compared to baseline 
64 
(unpublished data); however, it is not known if these changes will persist or return to baseline over time. 
65 
Preliminary unpublished data presented by investigators also treating hypoparathyroid subjects with PTH 
66 


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1-84 suggest that the increases in bone turnover may return to normal by 2 years on PTH therapy.10,11 
67 
Given this conflicting data, additional data is necessary, as there remains the possibility of compromised 
68 
bone quality and strength with long-term PTH therapy.  
69 
Although HPTH is not approved or marketed for use in hypoparathyroidism, a structurally identical drug, 
70 
recombinant human PTH (rhPTH, teriparatide, Forteo ®, Eli Lily and Co.) has been shown to restore 
71 
skeletal integrity and increase bone mass in the elderly population and was approved for treatment of 
72 
osteoporosis in 2002.12,13 Daily rhPTH treatment in the patients with osteoporosis has an anabolic effect 
73 
on cortical bone and improves cancellous bone microarchitecture.14 Whereas much information is 
74 
currently known about the effects of rhPTH on osteoporosis in the elderly and the NIH studies have 
75 
examined HPTH’s effects on calcium metabolism in hypoparathyroidism, very little is known about the 
76 
effects of HPTH on hypoparathyroid bone. This study is uniquely designed to address these questions. 
77 
Exploration of this area is important to elucidate the role of PTH in maintaining skeletal integrity, 
78 
especially in the setting of the recent availability of PTH for the off-label use of the treatment of 
79 
hypoparathyroidism. 
80 
This study was originally designed to evaluate the effects of twice verses three times daily HPTH 
81 
replacement on the skeleton of children and adults with hypoparathyroidism. However, preliminary data 
82 
from this study suggested that the effects of the two dosing regimens are similar, and new questions about 
83 
the long-term effects of HPTH therapy on bone have emerged. In addition, the previous version of this 
84 
protocol called for 3 to 4 iliac crest biopsies per subject, and concerns had been raised about subject 
85 
burden and the integrity of data from multiple biopsies on the same side of the iliac crest. Therefore, we 
86 
originally revised the protocol to allow for an examination of effects of HPTH over a 5-year period, 
87 
exclude children, and to reduce the number of biopsies to 2 per subject. 
88 
This document describes a revision to the original protocol (October 27, 2006 – April 28, 2009); this 
89 
current protocol (initially approved April 9, 2010) examines the effects of HPTH over a 5-year period, 
90 
reduces the number of biopsies to two per subject, and eliminates the comparison between twice-a-day 
91 
and three-times-a-day dosing of HPTH. This protocol uses twice-daily dosing only and will recruit a total 
92 
of 36 new subjects with hypoparathyroidism.  This protocol has also re-enrolled qualified subjects that 
93 
were on either conventional therapy (calcium and calcitriol) or HPTH therapy under the original protocol. 
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2 
STUDY OBJECTIVES 
95 
2.1 
Primary Objective 
96 
The primary objective of this study is to assess changes in static and dynamic bone histomorphometry 
97 
after 1 year, 2 years, and 4 years of HPTH therapy. 
98 
2.2 
Secondary Objectives 
99 
The secondary objectives are: 
100 
1. 
To explore changes in bone mineralization density distribution as assessed by quantitative back-
101 
scattered electron imaging after 1 year, 2 years, and 4 years of HPTH therapy. 
102 
2. 
To assess changes in serum and urine calcium, bone density, nephrocalcinosis, and biochemical 
103 
markers of bone metabolism over the course of HPTH therapy. 
104 
3. 
To explore whether the effects of HPTH on the microarchitectural characteristics of bone and 
105 
biochemical markers of bone and calcium metabolism differ by the presence or absence of the 
106 
calcium-sensing receptor mutation and other subject characteristics.  
107 
2.3 
Tertiary Objective 
108 
The tertiary objective is to assess early changes in blood chemistries and FGF23, renal mineral handling, 
109 
and PTH sensitivity with the initiation of HPTH in patients with hypoparathyroidism. 
110 
 
111 
3 
SUBJECTS 
112 
3.1 
Description of Study Populations 
113 
Under the current protocol, 36 new subjects (i.e., not previously enrolled) with physician-diagnosed 
114 
hypoparathyroidism who meet the revised eligibility criteria listed below will be enrolled. Previously 
115 
enrolled subjects who were on conventional therapy for hypoparathyroidism were re-evaluated under the 
116 
revised eligibility criteria and re-consented and re-enrolled if they were eligible and interested.  
117 
Previously enrolled subjects who were on HPTH therapy were re-consented and allowed to continue on 
118 
HPTH therapy in the current protocol as a separate group that would not enter the randomization nor have 
119 
any additional biopsies performed.  However, they will return to the NIH for 6-month follow-up visits 
120 
and assessments. Those subjects on HPTH at the time of re-consent were not re-assessed using the revised 
121 
criteria, and their study data will be analyzed separately from the other subjects’ data.  
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3.2 
Inclusion Criteria  
123 
1. 
Age eligibility at screening: 
124 
a. 
Premenopausal women: aged 18 to 45 years, 
125 
b. 
Postmenopausal women:  aged ≥ 53 years to 70 years and 5 years since last menses.  For 
126 
women without a uterus, subjects must have a clinical history of menopause for at least 5 
127 
years and an FSH > 30 U/L. 
128 
c.     Men: aged 18 to 70 years 
129 
2. 
Physician-diagnosed hypoparathyroidism of at least 1-year duration, confirmed by medical 
130 
record review.  The investigators will confirm the diagnosis during the screening visit at which 
131 
time the subject must have an intact PTH < 30 pg/mL. 
132 
3.3 
Exclusion Criteria  
133 
1. 
Moderate to severe hepatic disease defined as hepatic transaminases (ALT and AST) > 2 times 
134 
the upper limit of normal  
135 
2. 
Severe renal insufficiency defined as a calculated GFR < 25 mL/min/1.73 m2, using the CKD-
136 
EPI equation15. 
137 
3. 
Allergy or intolerance to tetracycline antibiotics 
138 
4. 
Pregnant or lactating or planning to become pregnant during the course of the study.  (Women 
139 
who are able to get pregnant must agree to use an effective form of birth control while in this 
140 
study.)  
141 
5. 
Perimenopausal defined by no menses for 6 months to 5 years and an FSH > 20 U/L at the 
142 
screening and/or baseline visits. 
143 
6. 
Chronic diseases that might affect mineral metabolism such as diabetes, celiac disease, Crohn’s 
144 
disease, Cushing’s syndrome, or adrenal insufficiency 
145 
7. 
Concurrent treatment with doses of thyroid hormone intended to suppress thyroid stimulating 
146 
hormone below the assay’s detection limit or persistent thyroid cancer 
147 
8. 
History of a skeletal disease unrelated to hypoparathyroidism, such as osteoporosis or low bone 
148 
density (defined as a DXA Z-Score < -2 in all subjects or T-score < -2 in subjects ≥  20 year 
149 
old),  osteosarcoma, Paget’s disease, alkaline phosphatase > 1.5 times the upper limit of 
150 
normal, or metastatic bone disease 
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9. 
History of retinoblastoma or Li-Fraumeni syndrome 
152 
10. 
History of treatment with bisphosphonates, calcitonin, tamoxifen, selective-estrogen receptor 
153 
modulators, or directed skeletal irradiation 
154 
11. 
Use of oral or intravenous corticosteroids or estrogen replacement therapy for more than 3 
155 
weeks within the last 6 months 
156 
12. 
Use of depot medroxyprogesterone for contraception within the past 12 months 
157 
13. 
Chronic inadequate biochemical control with conventional therapy and/or calcium infusion 
158 
dependent 
159 
14. 
Seizure disorder requiring antiepileptic medications 
160 
15. 
Treatment with PTH for more than 2 weeks continuously at any time, prior to study entry 
161 
16. 
Any cognitive impairment that limits the subject’s ability to comply, independently or through 
162 
the assistance of a legally authorized representative, with protocol procedures  
163 
17. 
Open epiphyses as determined by an X-ray of the hand and wrist in subjects < 21 years of age. 
164 
4 
STUDY DESIGN AND METHODS 
165 
4.1 
Study Overview 
166 
As revised in April 2010, the current protocol involves the recruitment of 36 new subjects (not previously 
167 
enrolled) with hypoparathyroidism and the re-enrollment of qualifying subjects from the original protocol 
168 
who were either on conventional therapy (calcium and calcitriol) or on HPTH therapy. All newly enrolled 
169 
subjects will be placed on conventional therapy for 2 to 6 months (± 1 month), have a baseline bone 
170 
biopsy performed at the start of HPTH therapy, and have their second biopsy performed after 1, 2, or 4 
171 
years of HPTH therapy, with the timing of the second biopsy determined by random assignment. The 
172 
subjects on conventional therapy under the previous version of the protocol were randomized to a second 
173 
biopsy at year 1, 2, or 4; however, their pre-conventional therapy biopsy will be used as their baseline 
174 
biopsy. Subjects who were receiving HPTH under the previous version of the protocol are being 
175 
maintained on HPTH in a separate group as a means to continue their care and to describe the effects of 
176 
HPTH therapy on bone and markers of bone metabolism over time. Those subjects will not have another 
177 
biopsy performed. All new and re-enrolled subjects will receive HPTH therapy for a maximum of 5 years. 
178 
Subjects will be initiated on HPTH at a starting dose of 0.2 μg/kg/dose subcutaneously twice a day. 
179 
Because HPTH will not be administered to subjects with open epiphyses, a bone x-ray will be conducted 
180 
on all subjects less than 21 years of age to confirm epiphyseal fusion. Subjects currently on HPTH 
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therapy 3 times per day under the previous version of the protocol will be placed on HPTH 2 times per 
182 
day, initially keeping the total daily dose the same. Over the 5-year course of HPTH therapy, the subjects 
183 
will have their blood and urine measured repeatedly and evaluated by the study investigators, who will 
184 
adjust subjects’ HPTH dosing according to a standardized algorithm. During HPTH therapy, subjects will 
185 
visit the NIH Clinical Center every 6 months for outcome assessments. At the conclusion of the 5-year 
186 
treatment period, subjects will be transitioned back to conventional care and followed for a minimum of 3 
187 
months before returning them to care under their own physicians.  All subjects, including those who 
188 
discontinue HPTH prior to 5 years, will be asked to return for a final, follow-up visit approximately 6 
189 
months after the start of the post-HPTH stabilization phase (i.e., the initiation of transition to conventional 
190 
care). 
191 
With a study period of approximately 6 years, the duration of the active phase of the study will be 9 years. 
192 
New subjects will have 13 NIH visits, subjects currently on conventional care will have 12 NIH visits, 
193 
and subjects currently on HPTH therapy will have up to 9 visits, depending on the amount of time they 
194 
have been treated with HPTH under the previous version of the protocol. Additional visits may occur in 
195 
order to evaluate adverse events. 
196 
The study design diagram and the schedule of events may be found in Appendix 24.3 and Appendix 24.4. 
197 
4.2 
Recruitment 
198 
It is estimated that new patient accrual will take approximately 8 years.  Recruitment strategies will 
199 
include IRB-approved advertising and direct contact with healthcare providers. Printed advertisements 
200 
may be sent to health care providers and patient support groups, such as the Hypoparathyroidism 
201 
Association. Interested individuals will contact the NIH Patient Recruitment and Public Liaison (PRPL) 
202 
via a toll free telephone number (800-411-1222) or email (prpl@mail.cc.nih.gov) to be prescreened for 
203 
the protocol using questions provided by the research team (Appendix 24.2). Individuals who are deemed 
204 
eligible by the PRPL staff will have their contact information forwarded to the study staff. In addition, the 
205 
current Clinicaltrials.gov listing for the study has been updated to reflect the current design of  the 
206 
protocol, and a recruitment website (http://www.hypoparathyroidstudy.org) containing IRB-approved 
207 
content is available on the internet.   
208 
4.3 
Screening  
209 
4.3.1 Pre-Screening 
210 
Potential subjects who have contacted the study team and indicated interest in the study will be pre-
211 
screened by telephone. During this phone pre-screen, study staff will briefly describe the study and 
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administer a pre-screening questionnaire (Appendix 24.2) to those who are interested in participating.  
213 
Patients who are eligible after completing the telephone pre-screen interview will be asked to arrange for 
214 
a copy of their medical records to be sent to the clinical site. Based on a review of their medical records, 
215 
further qualified subjects will be scheduled for an inpatient screening visit at the NIH Clinical Center to 
216 
obtain informed consent and then to further establish eligibility. 
217 
4.3.2 Inpatient Screening Visit 
218 
Newly recruited subjects (subjects not previously enrolled in this protocol) will attend a 2 to 3 day 
219 
inpatient screening visit at the NIH Clinical Center in order to obtain informed consent, to discuss 
220 
protocol procedures and expectations, to establish eligibility, and to optimize conventional therapy. 
221 
Procedures and tests during this inpatient screening visit will include: 
222 
1. 
History 
223 
a. 
Detailed history of disease 
224 
b. 
Current medications 
225 
c. 
Dietician consultation 
226 
d. 
Short Calcium Questionnaire (Appendix 24.5) 
227 
2. 
Physical Exam 
228 
a. 
Height and weight measurement 
229 
b. 
Vital signs (pulse, blood pressure, temperature, and respiratory rate) 
230 
c. 
Physical examination 
231 
3. 
Blood tests 
232 
a. 
Blood chemistries:  sodium, potassium, chloride, bicarbonate, creatinine, glucose, urea 
233 
nitrogen, albumin, calcium, magnesium, phosphorous, alkaline phosphatase, alanine 
234 
aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin, direct bilirubin, 
235 
LD, total protein, total CK, and uric acid 
236 
b. 
TSH and Free T4  
237 
c. 
25-OH vitamin D, 1,25 (OH)2 vitamin D, intact PTH 
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d. 
Complete blood count (CBC):  white blood cells (WBC), red blood cells (RBC), 
239 
hemoglobin, hematocrit, mean corpuscular volume (MCV), red cell distribution width 
240 
(RDW), and platelets   
241 
e. 
Mineral panel or calcium level (repeated as needed during the visit):  albumin, calcium, 
242 
magnesium, and phosphorous  
243 
f. 
Ionized calcium 
244 
g. 
DNA testing for genetic forms of hypoparathyroidism, if indicated (separate consent form, 
245 
Appendix 24.6) 
246 
4. 
Urine testing  
247 
a. 
Urine pregnancy test in females with childbearing potential 
248 
b. 
Urinalysis:  glucose, protein, urobilinogen, pH, hemoglobin, ketones, nitrite, leukocyte 
249 
esterase, appearance, specific gravity, color, RBC, WBC, and squamous cells 
250 
c. 
24-hour urine for calcium, phosphorus, creatinine, magnesium, sodium, citrate, pH, and 
251 
potassium  
252 
5. 
Imaging 
253 
a. 
Renal Ultrasound to assess the presence of nephrocalcinosis 
254 
b. 
Radiograph of hand and wrist to confirm epiphyseal fusion in subjects < 21 years of age 
255 
c.  DXA scan of the spine, femur, radius and total body to assess bone density 
256 
4.4 
Study Design 
257 
With respect to HPTH treatment, this study is a single group, within-subjects, repeated measures 
258 
treatment trial. With respect to all bone biopsy analyses, the design is a parallel group design with each 
259 
subject allocated to one of the 3 biopsy follow-up times:  1, 2 or 4 years after initiation of HPTH therapy.  
260 
Post-baseline biopsy timing will be randomly assigned (1:1.2:1.4, respectively) to each subject, stratified 
261 
by gender and by menopausal status, when relevant.  Changes from baseline (time 0) to 1, 2 and 4-years 
262 
will be compared.  Subjects who were on conventional therapy in the former version of the protocol will 
263 
also be randomized into the new study design. In contrast to new subjects, whose biopsy is performed at 
264 
the end of the conventional care run-in period, the pre-conventional care biopsy will be used as the 
265 
baseline for the those subjects entering the new design after having been on conventional care in the older 
266 
protocol. Because it is not known with certainty what effects duration of time on conventional therapy 
267 
will have on biopsy results, randomization will also be stratified on status of prior study participation. The 
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subjects who were on HPTH therapy at the time of the protocol redesign are followed as a separate group 
269 
under this protocol.  
270 
4.5 
Study Procedures 
271 
4.5.1 Conventional Therapy Prior to Start of HPTH 
272 
After the screening visit, newly enrolled subjects will complete a run-in period on conventional therapy of 
273 
calcium and calcitriol. The run-in period will last 2 to 6 months (± 1 month), depending on disease status 
274 
at enrollment and clinical response to optimized conventional therapy. During the run-in period, the 
275 
clinical investigators will provide conventional care for hypoparathyroidism, which includes periodic 
276 
blood and urine testing and adjustments in calcium and calcitriol dosing.   If necessary, thyroid hormone 
277 
replacement will be optimized.  Subjects may also receive vitamin D supplementation to ensure 25-OH-
278 
Vitamin D levels ≥ 25 ng/mL. 
279 
4.5.2 Inpatient Baseline Visit and Start of HPTH Therapy 
280 
This visit occurs at the end of the conventional therapy run-in period.  The purpose of this 7 to 10 day 
281 
inpatient visit is to obtain baseline clinical and research measurements, to perform a baseline biopsy, to 
282 
initiate the 5-year HPTH therapy, and to randomize subjects to the timing of their second biopsy. This 
283 
visit is only required for newly enrolled subjects and subjects currently on conventional care under the 
284 
previous version of the protocol. Both groups of subjects will complete the same procedures at this visit, 
285 
except for the consent process and the iliac crest biopsy. Subjects on conventional care from the previous 
286 
version of the protocol will be re-consented at this visit after a review of their eligibility; however, they 
287 
will not undergo a biopsy at this visit. Their pre-conventional therapy biopsy will be substituted for their 
288 
baseline biopsy. The newly enrolled subjects will undergo a baseline iliac crest biopsy at this visit. At the 
289 
baseline visit, the following procedures will be conducted: 
290 
1. 
History 
291 
a. 
Detailed history of current disease and adverse events 
292 
b. 
Current medications 
293 
c. 
Dietician consultation 
294 
d. 
Short Calcium Questionnaire (Appendix 24.5) 
295 
e. 
SF-36 Health Survey (Appendix 24.7) 
296 
2. 
Physical Exam 
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a. 
Height and weight measurement 
298 
b. 
Vital signs (pulse, blood pressure, temperature, and respiratory rate) 
299 
c. 
Physical examination 
300 
3.     Fitness measures 
301 
a. 
Fatigue Symptom Inventory (Appendix 24.8) 
302 
b. 
6-Minute Walk Test (Appendix 24.9) 
303 
4. 
Blood tests (IV catheter may be placed for convenience of drawing blood during this inpatient 
304 
visit) 
305 
a. 
Blood chemistries:  sodium, potassium, chloride, bicarbonate, creatinine, glucose, urea 
306 
nitrogen, albumin, calcium, magnesium, phosphorous, alkaline phosphatase, ALT,  AST, 
307 
total bilirubin, direct bilirubin, LD, total protein, total CK,  and uric acid 
308 
b. 
TSH and Free T4 
309 
c. 
25-OH vitamin D, 1,25 (OH)2 vitamin D*, intact PTH 
310 
d. 
CBC:  WBC, RBC, hemoglobin, hematocrit, MCV, RDW, and platelets   
311 
e. 
Research bloods for storage and potential future use (as yet undetermined) 
312 
f. 
Mineral panel or calcium level (performed and repeated as needed):  albumin, calcium, 
313 
magnesium, phosphorous* 
314 
g. 
Bone-specific alkaline phosphatase  
315 
h. 
Osteocalcin 
316 
i. 
Ionized calcium 
317 
j.      FGF23* 
318 
k.    Acute care panel*  
319 
*Blood draws for an acute care panel, mineral panel, 1,25 (OH)2 vitamin D, and FGF23 will be 
320 
completed at 8AM, 12PM, 4PM, and 8PM on the first day of HPTH therapy (Day 0). Blood 
321 
draws for an acute care panel, mineral panel, 1, 25 (OH)2 vitamin D, and FGF23 will also be 
322 
collected at 8AM on the second day of HPTH therapy (Day 1). A morning blood draw will be 
323 
completed on subsequent in-patient days for an acute care panel. 
324 
5. 
Urine testing  
325 
a. 
Urine pregnancy test in females with childbearing potential 
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b. 
Urinalysis:  glucose, protein, urobilinogen, pH, hemoglobin, ketones, nitrite, leukocyte 
327 
esterase, appearance, specific gravity, color, RBC, WBC, and squamous cells 
328 
c. 
Two 24-hour urine collections for testing of calcium, phosphorus, creatinine, magnesium, 
329 
sodium, citrate, N-telopeptide, pH, and potassium 
330 
d.     Spot urine for cAMP, creatinine, phosphorous, calcium, and pH 
331 
6. 
Imaging 
332 
a. 
Renal ultrasound to assess the presence of nephrocalcinosis 
333 
b. 
CT of the kidney without contrast to assess the presence of nephrocalcinosis 
334 
c. 
DXA scan of the spine, femur, radius and total body to assess bone density 
335 
d. 
Quantitative CT of the L1 and L2 spine to assess bone density 
336 
7. 
Baseline bone biopsy for newly enrolled subjects (see Section 4.5.6) 
337 
8. 
Randomization of newly enrolled subjects and previously enrolled conventional care subjects to 
338 
a second biopsy after 1, 2, or 4 years of HPTH therapy. A dynamic allocation scheme will be 
339 
used to ensure balance across biopsy arms by gender, menopausal status, and prior participation 
340 
in the protocol (see Section 10.3). The principal investigator or designee will perform the 
341 
randomization procedure using a secure, web-based randomization system.  
342 
All subjects will receive HPTH at a starting dose of 0.2 μg/kg/dose subcutaneously twice a day. After the 
343 
initial dosing, HPTH will be titrated based on serum calcium levels, according to the dosing algorithm in 
344 
Appendix 24.10. Each subject will receive education and written materials about HPTH administration 
345 
and dosing adjustment prior to discharge (Appendix 24.11). The drug will be provided to all subjects free 
346 
of charge. The NIH Clinical Center Pharmaceutical Development Service (PDS) will be responsible for 
347 
labeling, storing, preparing, dispensing, and maintaining accountability records for HPTH. 
348 
4.5.3 Follow-up Visits During HPTH Therapy 
349 
Subjects will be seen at the NIH every 6 months (± 2 weeks) until they have completed up to 5 years of 
350 
HPTH therapy. The second biopsy will occur at one of these visits, with the timing of that biopsy 
351 
determined by random assignment. Subjects currently on HPTH therapy under the previous version of the 
352 
protocol will be re-consented at the first follow-up visit they attend. Follow-up visits may be conducted 
353 
on an inpatient or outpatient basis at the discretion of the investigator, except for biopsy visits which must 
354 
be inpatient. Follow-up visits will last 1-3 days if a biopsy is not being performed and 5-7 days if a biopsy 
355 
is being performed. Additional visits may be scheduled at the discretion of the investigator in order to 
356 


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assess adverse events or other problems that may arise. All subjects will undergo the procedures and tests 
357 
described below at each follow-up visit, unless otherwise noted: 
358 
1. 
History 
359 
a. 
Detailed history of current disease and adverse events 
360 
b. 
Current medications 
361 
c. 
Dietician consultation 
362 
d. 
Short Calcium Questionnaire (Appendix 24.5) 
363 
e. 
SF-36 Health Survey (Appendix 24.7). 
364 
2. 
Fitness measures 
365 
a. 
Fatigue Symptom Inventory (Appendix 24.8) 
366 
b. 
6-Minute Walk Test (Appendix 24.9) 
367 
3. 
Physical Exam 
368 
a. 
Height and weight measurement 
369 
b. 
Vital signs (pulse, blood pressure, temperature, and respiratory rate) 
370 
c. 
Physical examination 
371 
4. 
Blood tests 
372 
a.    Blood chemistries:  sodium, potassium, chloride, bicarbonate, creatinine, glucose, urea 
373 
nitrogen, albumin, calcium, magnesium, phosphorous, alkaline phosphatase, ALT,  AST, 
374 
total bilirubin, direct bilirubin, LD, total protein, total CK,  and uric acid 
375 
b. 
TSH and Free T4 
376 
c. 
25-OH vitamin D, 1,25 (OH)2 vitamin D, intact PTH 
377 
d. 
CBC:  WBC, RBC, hemoglobin, hematocrit, MCV, RDW, and platelets   
378 
e. 
Research bloods for storage and potential future use (as yet undetermined) 
379 
f. 
Mineral panel or calcium level (performed and repeated as needed):  albumin, calcium, 
380 
magnesium, phosphorous 
381 
g. 
Bone-specific alkaline phosphatase  
382 
h. 
Osteocalcin 
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i. 
Ionized calcium 
384 
j. 
Twenty-four hour blood sampling:  Every 2-hour ± 15 min sampling (for 24 hours) for calcium, 
385 
magnesium, phosphorus, and albumin will be done after 1 year on PTH. An IV catheter or PICC 
386 
line may be placed for convenience of drawing blood during this inpatient visit. 
387 
5. 
Urine testing  
388 
a. 
Urine pregnancy test in females with childbearing potential 
389 
b. 
Urinalysis:  glucose, protein, urobilinogen, pH, hemoglobin, ketones, nitrite, leukocyte 
390 
esterase, appearance, specific gravity, color, RBC, WBC, and squamous cells 
391 
c. 
Two 24-hour urine collections for testing of calcium, phosphorus, creatinine, magnesium, 
392 
sodium, citrate, N-telopeptide, pH, and potassium 
393 
6. 
Imaging - to be done at the start of PTH therapy and then annually (with the exception of the 
394 
DXA) 
395 
a. 
Renal ultrasound to assess the presence of nephrocalcinosis  
396 
b. 
CT of the kidney without contrast to assess the presence of nephrocalcinosis 
397 
c. 
DXA scan of the spine, femur, radius and total body – every visit to assess bone density 
398 
d. 
Quantitative CT of the L1 and L2 spine to assess bone density 
399 
7. 
Second and final bone biopsy at one of the visits (see Section 4.5.6) 
400 
4.5.4 Outpatient Blood and Urine Collections 
401 
All subjects will be given a laboratory slip to be used at their local laboratory for measurement of serum 
402 
calcium and 24-hour urine calcium, sodium, and creatinine. Subjects will be instructed to obtain blood 
403 
tests at least once a week (± 2 days) immediately after starting PTH therapy. After 4 consecutive serum 
404 
calcium levels within the target range, subjects will be instructed to obtain blood work a minimum of 
405 
once a month (± 1 week). Urine collections should be obtained approximately every 3 months (± 2 
406 
weeks). Additional outpatient blood or urine tests may be ordered as clinically indicated.  Participants will 
407 
be instructed to have lab results sent to the research team. The principal investigator or designee will 
408 
review the results of these tests, adjust medication doses, and order additional testing according to the 
409 
HPTH dosing algorithm (Appendix 24.10). Prior to making any dose adjustment decision, the investigator 
410 
will assess the subject’s adherence to medication instructions. The investigator will record all dosing 
411 
decisions, along with the laboratory values associated with those decisions. 
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4.5.5 Monitoring of Calcium-Citrate Ratio and Concomitant Potassium Citrate  
413 
All subjects will be monitored for hypocitraturia during the inpatient visits.  As hypocitraturia may 
414 
increase the risk of renal calcifications, subjects with a urinary calcium/citrate ratio greater than 0.7 will 
415 
receive potassium citrate supplementation, in attempt to lower this ratio.  It should be noted that complete 
416 
normalization of the urinary citrate excretion and reduction of the calcium/citrate may be impossible in 
417 
these subjects, due to chronic renal tubular dysfunction associated with this disease.  Urinary citrate and 
418 
pH will be monitored on the outpatient collection, as well as during the NIH visits, in subjects treated 
419 
with potassium citrate.  If the urinary pH rises above 7, adjustments to potassium citrate dosing may be 
420 
made after consultation with the nephrologist on the study team. 
421 
 
422 
4.5.6 Bone Biopsy Procedures 
423 
Two percutaneous transiliac crest biopsies will be performed after antibiotic labeling, with one biopsy 
424 
performed prior to HPTH therapy and the second during HPTH therapy. The biopsy will be performed by 
425 
a licensed practitioner credentialed in this procedure in the operating room of the NIH Clinical Center 
426 
under local anesthesia with sedation. The baseline and second biopsy will be obtained from opposite 
427 
sides. Subjects will be pre-treated with either tetracycline or demeclocycline. Tetracycline will be 
428 
delivered according to the following schedule: 3 days of tetracycline (250 mg 4 times per day), 12 days 
429 
off drug, 3 days of tetracycline (250 mg 4 times per day), 4 days off drug and biopsy on the fifth day (+ 7 
430 
days).  Demeclocycline will be delivered according to the following schedule: 3 days of demeclocycline 
431 
(150 mg 4 times per day), 12 days off drug, 3 days of demeclocyline (150 mg 4 times per day), 4 days off 
432 
drug and biopsy on the fifth day (+ 7 days). Refer to Appendix 24.12 for details.  The biopsy is performed 
433 
through a small skin incision (approximately 4 cm), which is closed with stitches that will dissolve within 
434 
2 to 3 weeks. The skin over the area of the hip will be cleaned and a numbing medication will be injected 
435 
with a small needle into the skin, through the underlying tissues, and onto the surface of the bone. A 
436 
trephine with a 7.5 mm diameter is used to remove the bone specimen.  Subjects will undergo a routine 
437 
pre-anesthesia consult and be asked to sign a separate surgical consent form prior to the procedure. 
438 
4.6 
 End of Participation  
439 
4.6.1 Post HPTH Therapy Stabilization and Follow-up 
440 
For subjects completing 5 years of HPTH therapy and for subjects who meet withdrawal or treatment 
441 
failure criteria during the study (see Section 8), the study team will provide care for a minimum of 3 
442 
months (± 2 weeks) and until the investigator deems them to be stable and ready for transition to local 
443 


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physicians. During this stabilization phase, subjects will be restarted on calcitriol and calcium 
444 
supplements and HPTH will be gradually weaned as tolerated to keep calcium levels within the target 
445 
range.  Subjects will undergo periodic blood testing via their local lab (at minimum bi-weekly during the 
446 
stabilization phase). These lab values will be used to guide adjustments in calcium and calcitriol dosing.   
447 
All subjects who receive HPTH therapy for more than 6 months will be asked to return to the clinic to 
448 
complete a follow-up visit 6 months (± 2 weeks) after the start of the post-HPTH stabilization phase.  All 
449 
subjects will undergo the procedures and tests described below during the follow-up visit: 
450 
1.     History 
451 
a. 
Detailed history of current disease and adverse events 
452 
b. 
Current medications 
453 
c. 
Dietician consultation 
454 
d. 
Short Calcium Questionnaire (Appendix 24.5) 
455 
e. 
SF-36 Health Survey (Appendix 24.7). 
456 
2. 
Fitness measures 
457 
a. 
Fatigue Symptom Inventory (Appendix 24.8) 
458 
b. 
6-Minute Walk Test (Appendix 24.9) 
459 
3. 
Physical Exam 
460 
a. 
Height and weight measurement 
461 
b. 
Vital signs 
462 
c. 
Physical examination 
463 
4. 
Blood tests 
464 
a. 
Chemistry 20 panel 
465 
b. 
Thyroid panel 
466 
c. 
25-OH vitamin D, 1,25 (OH)2 vitamin D, intact PTH 
467 
d. 
CBC 
468 
e. 
Research bloods for storage and potential future use (as yet undetermined) 
469 
f. 
Mineral panel or calcium level (performed and repeated as needed) 
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g. 
Bone-specific alkaline phosphatase  
471 
h. 
Osteocalcin 
472 
i. 
Ionized calcium 
473 
5. 
Urine testing  
474 
a. 
Urine pregnancy test in females with childbearing potential 
475 
b. 
Urinalysis 
476 
c. 
Two 24-hour urine collections for testing of calcium, phosphorus, creatinine, magnesium, 
477 
sodium, citrate, N-telopeptide, pH, and potassium 
478 
6. 
Imaging  
479 
a. 
DXA scan of the spine, femur, radius and total body  
480 
b.    Renal Ultrasound   
481 
See Section 4.7 for details of post-study transition to primary care physician. 
482 
4.7 
Communication with Referring Physicians 
483 
With written consent of the subjects, referring physicians will receive clinical information about the 
484 
health status of subjects during the trial on an as-needed basis. At the conclusion of the post-HPTH 
485 
stabilization phase, local physicians will be provided with clinical summaries of the current health status 
486 
of the subjects, as well as information about any medically relevant, untoward events that occurred during 
487 
the trial. 
488 
5 
STORAGE OF DATA AND SAMPLES   
489 
5.1 
Data 
490 
Study staff will complete electronic case report forms (eCRFs) via a web-based electronic data capture 
491 
(EDC) system that is compliant with Part 11 Title 21 of the Code of Federal Regulations. The EDC is 
492 
housed on a secure server at Rho, Inc. in North Carolina.  The Principal Investigator is responsible for 
493 
management of study related records at the completion of the protocol.  The investigators will retain all 
494 
study-related records for at least 2 years after discontinuation of the study and as required by regulation. 
495 
5.2 
Samples 
496 
Research samples collected from subjects consented to this protocol will be stored in locked freezers 
497 
belonging to the Craniofacial and Skeletal Diseases Branch located in Building 30 on the NIH Bethesda 
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campus. A section of the bone specimen will be shipped to non-NIH investigators at the Helen Hayes 
499 
Hospital and the Ludwig Boltzmann Institute of Osteology for analysis (see Section 9.1 for outcome 
500 
measures derived from these analyses). The non-NIH investigators may return portions of these bone 
501 
specimens to NIH where they will be maintained in a secure location that is only accessible to the study 
502 
team. A label will be applied to each research sample containing the subject ID, collection date, and 
503 
specimen type.   Study staff will use a computer-based specimen tracking system, accessed via secure 
504 
NIH servers. The system will be used to document sample collection, notify laboratories of shipments, 
505 
track shipments, and provide details on the disposition of all samples. 
506 
5.2.1  Samples and Data Management after Completion of the Protocol   
507 
The principal investigator is responsible for management of samples and data at the completion of the 
508 
protocol. Samples will be destroyed at the end of the protocol unless there has been IRB approval to 
509 
retain them. 
510 
5.2.2  Research Collaborations Involving Stored Specimens or Data   
511 
The Principal Investigator will seek NIH IRB review and approval for research collaborations in which 
512 
coded samples are sent to non-NIH investigator(s). She will identify the names of the collaborating 
513 
researchers and their affiliated institutions, as well as intended plans for use. 
514 
6 
ADDITIONAL CONSIDERATIONS 
515 
6.1 
Research with Investigational Drugs or Devices 
516 
6.1.1 Synthetic Human Parathyroid Hormone (HPTH) 
517 
Synthetic human parathyroid hormone 1-34 (HPTH) is the first 34 amino acids of the intact 84-amino 
518 
acid parathyroid hormone. This peptide fragment, which contains all of the hormone’s biological activity, 
519 
was first synthesized in the early 1970’s.16 HPTH acts by binding to the PTH receptors in the bone to 
520 
mobilize calcium. It also acts on the kidney to increase calcium reabsorption, increase phosphate 
521 
excretion, and stimulate the enzyme 1-α-hydroxylase to convert 25-OH-Vitamin D to its active form, 
522 
1,25-OH2-Vitamin D. The main goal of hormone replacement therapy with HPTH is the simultaneous 
523 
normalization of serum and urine calcium, phosphorus, magnesium and markers of bone turnover. This 
524 
drug has not been approved by the FDA for the treatment of hypoparathyroidism. An Investigational New 
525 
Drug Application has been obtained for the investigational use of HPTH in this study. 
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6.1.2 Pharmacokinetics 
527 
Detailed pharmacokinetics are known about HPTH as well as rhPTH 1-34, which is structurally identical 
528 
to HPTH.17-19 It is well absorbed after subcutaneous injection with 95% becoming bioavailable. Peak 
529 
concentrations are reached at approximately 30 minutes after subcutaneous injection and gradually 
530 
decline to non-quantifiable levels within 3 hours. The half-life of HPTH injected subcutaneously is 
531 
approximately 60-75 minutes.  HPTH is metabolized by the liver and excreted by the kidneys. While the 
532 
drug has not been studied in patients with chronic renal failure or on dialysis, the pharmacokinetics do not 
533 
appear to be altered in patients with mild to moderate renal insufficiency (creatinine clearance: 30 – 72 
534 
mL/min). The drug has not been studied in patients with hepatic insufficiency. 
535 
6.1.3 Pharmacodynamics 
536 
In euparathyroid adults with osteoporosis, subcutaneous HPTH induces a rapid decrease in serum 
537 
phosphate followed by a later rise in serum calcium occurring between 90 and 120 minutes after injection, 
538 
associated with an increase in 1,25-OH2 Vitamin D levels.19 Urine calcium excretion also increases in 
539 
patients with osteoporosis, particularly with higher doses of HPTH, which were also associated with more 
540 
prolonged increases in urinary calcium.20 However, frank hypercalciuria was not noted with rhPTH in 
541 
more recent randomized-placebo controlled trial of post-menopausal women.12   In the NIH experience, 
542 
serum calcium peaked 3-4 hours and 1,25-OH2 Vitamin D peaked 8 hours after a subcutaneous 
543 
injection.2,3 
544 
6.1.4 Formulation and Preparation 
545 
HPTH is formulated from GMP grade raw material obtained from Bachem Americas Inc, in Torrance, 
546 
California. In the NIH Pharmacy, the formulation is made in a 5% D-mannitol solution, sterilized and 
547 
packaged in 2 mLType I glass vials with Teflon stoppers. The vials are tested for sterility, pyrogenicity, 
548 
peptide content and other factors before being released for patient use. The vials contain 1.0 mL of HPTH 
549 
in frozen, sterile solution to be used for injection only. In the past, subjects have been supplied with either 
550 
50 μg/mL or 200 μg/mL concentrations of HTPH, depending on their dosing level. Under the revised 
551 
protocol, all enrolled subjects will be supplied with HPTH in a 100 μg/mL concentration, including those 
552 
subjects who are already receiving HPTH.  
553 
6.1.5 Storage, Stability, and Handling 
554 
Intact vials of HPTH, 100 mcg, are projected to be stable for at least 24 months when stored in the freezer 
555 
(at or below -70ºC) and for at least 6 months when stored in the freezer (-25ºC to -10ºC). 
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Since HPTH contains no antibacterial preservatives, it should be used within 24 hours of initial entry to 
557 
the vial. Patients may remove 3 doses from 1 vial of HPTH if the vial is kept refrigerated and it is used 
558 
within a 24-hour period.  
559 
HPTH vials are stable through a freeze-thaw-freeze cycle. Vials that have been left at controlled room 
560 
temperature (15ºC to 30ºC) for up to 48 hours may be returned to the freezer for long-term storage.  
561 
6.1.6 Packaging and Labeling 
562 
HPTH is packaged and labeled by the PDS in 100 μg/mL vials, using a lot of HPTH that is designated for 
563 
use in the study. Subjects are provided with a 6-month supply of study drug at each visit. The vials are 
564 
dispensed in a sealed plastic bag.  
565 
The vial label contains the following elements: 
566 
x Name and address of the PDS  
567 
x Name and strength of the drug 
568 
x Lot number  
569 
x Statement that the drug is for investigational use only 
570 
The packaging label contains the following elements: 
571 
x Name of the prescribing physician  
572 
x Instructions for use  
573 
x Subject name and medical record number 
574 
x Date dispensed  
575 
x Storage requirements 
576 
6.1.7 Receipt, Dispensation, and Return of Clinical Supplies 
577 
HPTH will be received and dispensed by designated PDS staff according to PDS Standard Operating 
578 
Procedures. The PDS staff will document receipt and dispensation of investigational product on drug 
579 
accountability logs. The records of receipt will identify the name, lot number, and expiration date of the 
580 
product, the amount received, and the date and time of receipt. The dispensation records will identify the 
581 
name, lot number, and expiration date of the product, as well as the identification number of subjects and 
582 


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the quantity of drug dispensed to each subject. Accidental or intentional destruction of the investigational 
583 
product will also be documented. All records will be available for inspection by the clinical trial monitor. 
584 
The investigational product will be dispensed to the subjects at each visit, beginning with the baseline 
585 
visit. Each subject will receive a 6-month supply of HPTH. The drug supply will be enclosed in a 
586 
container with cold packs to maintain stability. Subjects will not be asked to return used and unused vials 
587 
at each visit or at the conclusion of the study.  
588 
6.1.8 Investigational Product Administration 
589 
All subjects will receive educational and written materials about the use of the investigational product. 
590 
The principal investigator and research nurses will provide training at the baseline visit and as needed at 
591 
subsequent visits. Subjects will also receive ongoing education about the appropriate methods for storing, 
592 
handling, and disposing of the investigational product in the home setting. All subjects will be provided 
593 
with the appropriate syringes and needles necessary to administer the investigational product. 
594 
6.2 
Gene Therapy 
595 
Not applicable. 
596 
7 
RISKS / DISCOMFORTS 
597 
7.1 
Assessment/Procedures with no Risks or Noteworthy Discomfort 
598 
The following assessments/procedures are deemed to have no risks and to cause no noteworthy 
599 
discomfort: collection of medical history, including concomitant medications, dietician consultation, and 
600 
short calcium questionnaire; physical examination (including vital signs); SF-36, and the fatigue symptom 
601 
inventory 
602 
7.2 
6-Minute Walk Test 
603 
 The 6-minute walk test may result in tiredness. A rehabilitation specialist will be present throughout the 
604 
test. 
605 
7.3 
Blood Draws 
606 
The total amount of blood drawn throughout the study will be 604 ml over a 6 year period; per the 
607 
protocol blood draw schedule (Appendix 24.14). The maximum amount of blood drawn during one study 
608 
visit will be 91 mL and the maximum amount drawn over an 8-week period will be 123 mL.  This amount 
609 
is less than the NIH guidelines of 10.5 ml/kg/8 weeks (< 550 mL) for adults.  Drawing blood for the tests 
610 
and placement of IV catheters may cause discomfort or a bruise at the injection site, and rarely, an 
611 


PI name: Rachel I. Gafni 
 
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infection may occur. Blood drawing by experienced personnel limits the risk of excessive pain, bruising 
612 
and infection. Twenty-four hour blood sampling is inconvenient to the subject and will cause sleep 
613 
disruption. Sampling will be done through an indwelling catheter, PICC line, or repeated venipuncture. 
614 
Indwelling catheterization is associated with a very small risk of infection. 
615 
7.4 
72BDNA Testing 
616 
Patients may be asked to undergo DNA testing to evaluate for possible genetic causes of 
617 
hypoparathyroidism, if not done previously. There is the possibility that DNA testing may lead to 
618 
unexpected discoveries, such as non-paternity. In addition, information gained by genetic analysis could 
619 
possibly lead to yet unknown discrimination, for example, difficulty in obtaining life insurance. Any 
620 
information gained in this analysis is confidential and will not be disclosed to any person or institution not 
621 
collaborating in this research effort, unless consent is provided by the patient. Results of genetic tests may 
622 
be placed in the medical record. 
623 
7.5 
Urine Collection 
624 
Urine collections may be an inconvenience to the patient, but collections are not associated with any 
625 
discomfort or risks. 
626 
7.6 
Renal Ultrasound   
627 
Renal ultrasounds are not associated with any risks; however, lying on a hard table may be 
628 
uncomfortable. 
629 
7.7 
Radiation 
630 
Renal and spinal CT and DXA scan contribute to total radiation of the study.  The "Effective Dose 
631 
Equivalent" is the sum of the absorbed radiation dose to the 5 organs, other than the skin, which receive 
632 
the highest doses: testes, ovaries, red bone marrow, lungs, and kidneys.  The total effective radiation dose 
633 
in this study is 1.1 rem, which is below the 5.0 rem per year NIH Radiation Safety Committee (RSC) 
634 
guideline for adults. 
635 
7.8 
Tetracycline Antibiotics for Bone Biopsy Labeling 
636 
Some patients experience side effects such as nausea, vomiting, diarrhea, and hypersensitivity reactions in 
637 
response to tetracycline antibiotics. Exposure to sunlight while taking tetracycline antibiotics can cause 
638 
skin eruptions and should be avoided. Subjects are informed of the cautions to be exercised in taking 
639 
tetracycline antibiotics and are instructed not to take these medications if they may be pregnant. 
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7.9 
Trans-iliac Crest Bone Biopsy 
641 
Subjects may experience discomfort and pain at the biopsy site for several days and can be treated safely 
642 
with acetaminophen or more potent analgesics as needed. Bleeding and infection at the site of biopsy are 
643 
possible but rare. Subjects may experience some transient anesthesia-related symptoms such as nausea, 
644 
vomiting, decreased appetite, fatigue, and decreased blood pressure. Subjects will undergo a routine pre-
645 
anesthesia consult and be asked to sign a separate surgical consent form prior to the procedure. 
646 
7.10 HPTH  
647 
7.10.1 FDA-Approval 
648 
There are no PTH preparations that are FDA-approved for the treatment of hypoparathyroidism. 
649 
Recombinant human PTH 1-34 (rhPTH) (teriparatide, Forteo®) is FDA-approved for the treatment of 
650 
osteoporosis. rhPTH and HPTH are structurally identical, with rhPTH being manufactured by 
651 
recombinant DNA technology and HPTH being manufactured by direct synthesis. An Investigational 
652 
New Drug Application has been obtained for the investigational use of HPTH in this study. 
653 
7.10.2 Carcinogenesis, Mutagenesis, and Reproductive Toxicology 
654 
Administration of high-dose teriparatide (rhPTH) for 2 years to euparathyroid Fischer 344 rats 
655 
demonstrated a dose and duration-related increase in osteosarcomas, osteoblastomas, and osteomas 
656 
associated with a large increase in bone mass and focal osteoblast hypoplasia.21 Similar studies in 
657 
macaques did not replicate this finding, 22 and the relevance of these rat studies to humans is unclear. 
658 
There have been 2 reports of humans treated with rhPTH developing osteosarcoma; however, causality 
659 
has not been established.23,24   The package labeling for rhPTH includes a black box warning stating that 
660 
teriparatide should not be used in individuals with an increased baseline risk of osteosarcoma including 
661 
those with a Paget’s disease, children or young adults with open epiphyses, or history of radiation therapy 
662 
to the skeleton.   To eliminate the confounding effects of the pubertal growth spurt, we have excluded 
663 
pediatric enrollment.  All subjects less than 21 years of age will undergo a bone x-ray to ensure 
664 
epiphyseal fusion.  Additionally, they recommend that individuals with a history of skeletal malignancies 
665 
or metabolic bone diseases other than osteoporosis not receive teriparatide treatment beyond 2 years.18   
666 
In vivo and in vitro mutagenesis studies were negative. There was no effect on male or female fertility in 
667 
rats given up to 160 times the equivalent human dose. In pregnant rats, teraparitide induced mild growth 
668 
retardation and reduced motor activity in the offspring. Affect on human fetal development and presence 
669 
in breast milk have not been studied; therefore rHPTH is not indicated for use in pregnant or lactating 
670 
women.18  
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7.10.3 Drug Interactions 
672 
There are no known drug interactions with HPTH. However, hypercalcemia from overdosage with 
673 
teriparatide may predispose patients to digitalis toxicity.18 
674 
7.10.4 Adverse Events 
675 
The safety of parathyroid hormone replacement therapy has been demonstrated in clinical trials involving 
676 
the treatment of hypoparathyroidism and osteoporosis. In a long-term NIH study comparing HPTH to 
677 
conventional care for the treatment of hypoparathyroidism, there were no significant differences between 
678 
treatment groups in the incidence of most adverse events, such as neuromuscular irritability, fatigue, or 
679 
arthralgias.5 Mild intermittent bone pain in the lower extremities occurred in 7 subjects receiving HPTH 
680 
and in 3 subjects receiving conventional care. The most common adverse events (>10% of subjects) 
681 
observed in clinical trials of rhPTH for osteoporosis included arthralgia, pain, and nausea. Another 
682 
common adverse event in these trials was the development of hypercalcemia. In this study, an increase in 
683 
serum calcium is a desired pharmacologic effect and would not be considered an AE, unless serum 
684 
calcium > 11 mg/dL persisted for more that 4 weeks. Transient orthostatic hypotension has been 
685 
infrequently observed in subjects treated with rhPTH for osteoporosis. This event typically occurred 
686 
within 4 hours of dosing and resolved spontaneously.18 Additional information about other adverse events 
687 
is available in the Forteo® package insert (Appendix 24.13). 
688 
Resistance to PTH and anti-PTH antibodies have been reported in 3% of women treated with rhPTH.18 In 
689 
patients with hypoparathyroidism, PTH resistance would manifest by diminishing responsiveness to the 
690 
therapy that will require increasingly greater doses of PTH to maintain normal serum calcium. Among the 
691 
subjects who develop resistance, many will be able to continue therapy if the resistance is small or partial. 
692 
Others may develop substantial resistance with unstable serum calcium and phosphate levels. PTH 
693 
therapy will be discontinued in those subjects, and those subjects will be withdrawn from the study after 
694 
returning them to conventional therapy (see Section 4.6).  
695 
Decreases in BMD of the radius, as measured by DXA, have been noted in preliminary data from this 
696 
protocol25 and other studies treating hypoparathyroid subjects with HPTH5 and PTH 1-8410 . 
697 
Histomorphometric analysis has also shown an increase in cortical porosity11,25,26.  Decreases in radial 
698 
BMD have been reported in euparathyroid postmenopausal women treated with rhPTH 1-34 without an 
699 
apparent increase in wrist fractures12 or change in cortical porosity 14.  The clinical relevance of these 
700 
changes in radial BMD in hypoparathyroid treated with HPTH is unknown.  Thus, this protocol excludes 
701 
and withdraws subjects with DXA BMD T-scores or Z-scores < -2. 
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Date:  September 9, 2015 
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Since this study has started, hypocitraturia (defined as a urine calcium to citrate ratio > 0.7 mg/mg) has 
703 
been observed in many subjects initiation of HPTH therapy.  Of note, some subjects also had elevated 
704 
urine calcium/citrate ratios prior to the initiation of HPTH.   Hypocitraturia has not been previously 
705 
reported in hypoparathyroidism and, to our knowledge, urine citrate has not been assessed in other studies 
706 
using PTH 1-34 or PTH 1-84 in the treatment of hypoparathyroidism.  Thus, the risk of hypocitraturia-
707 
associated nephrocalcinosis or nephrolithiasis in this patient population, on conventional or PTH therapy, 
708 
is not known. The urine calcium/citrate ratio will be monitored throughout the study and subjects will be 
709 
treated with potassium citrate, as tolerated, as described in section 4.5.5.   
710 
There is a risk of unforeseen adverse effects with every new drug treatment. The risks of participation are 
711 
reasonable relative to the significant health benefits and medical knowledge that may be achieved. 
712 
8 
SUBJECT SAFETY MONITORING 
713 
Subjects will be informed that they may choose to withdraw or the investigator may remove them if it is 
714 
in the subjects’ best interest or if the subjects are unable to complete the required assessments. Voluntary 
715 
withdrawal from the protocol is always an option for the research participants. As described throughout 
716 
Section 4.5, subjects will have blood and urine measured and evaluated by the study investigators on an 
717 
ongoing basis, and HPTH dosing will be adjusted according to a standardized dosing algorithm. The 
718 
principal investigator or designee will evaluate all clinical laboratory results for clinically significant 
719 
abnormalities and document the evaluation on a CRF. Clinically significant laboratory findings will be 
720 
recorded and reported as AEs (see Appendix 24.1) regardless of their association with the use of the 
721 
investigational product. 
722 
At each study visit, the study investigator will inquire about the occurrence of any AEs since the last visit. 
723 
The principal investigator will also review all source documentation related to inpatient study procedures 
724 
for evidence of AEs. Events will be followed until they return to baseline, until follow-up is no longer 
725 
medically necessary, or until the end of the AE surveillance period. 
726 
The following conditions will require the withdrawal of a subject from the HPTH therapy:  
727 
x Pregnancy 
728 
x New-onset illness requiring chronic use (> 3 weeks) of a medication that affects the bone such as 
729 
oral glucocorticoids, growth hormone, suppressive doses of thyroid hormone, estrogen or 
730 
testosterone. Inhaled, topical, and intranasal glucocorticoids are permitted. 
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PI name: Rachel I. Gafni 
 
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Version: 17.0 
 
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x Women who enter menopause after initiation of HPTH therapy will not be withdrawn from the 
732 
study unless they require hormone replacement therapy for > 3 weeks.  
733 
x Use of depot medroxyprogesterone for contraception. Subjects wishing to use oral, transdermal, 
734 
intravaginal, or intrauterine hormonal contraceptives may remain in the study. 
735 
x Significant deterioration in metabolic control on PTH as defined by repeated measurements of 
736 
serum calcium < 7 mg/dL for more than 4 weeks. 
737 
x Severe chronic bone pain or other unexpected new-onset chronic medical condition that cannot be 
738 
explained and may be related to PTH therapy 
739 
x Development of DXA or QCT Z-Score or T-score < -2.  As peak bone mass is not achieved until 
740 
the third decade of life, subjects beginning PTH before age 20 will only have Z-score assessed for 
741 
withdrawal determination. 
742 
x Decline in calculated GFR of < 25 mL/min/1.73 m2 or decline in calculated GFR by 25 
743 
mL/min/1.73m2 without clear etiology that persists on three monthly measurements (measured at 
744 
the NIH or the subject’s local laboratory).  
745 
x Increase in hepatic transaminases (ALT and AST) > 2x the upper limit of normal  
746 
x Treatment failure as defined by significant metabolic deterioration 
747 
x Recurrence of thyroid cancer in subjects with history of thyroid cancer 
748 
x Subject noncompliance with study procedures.  
749 
x Investigator judgment based on subject’s best medical interest 
750 
Subjects who require discontinuation of HPTH therapy will be gradually weaned off HPTH while 
751 
therapeutic doses of calcitriol and calcium are established as described in Section 4.5.5.  
752 
9 
OUTCOME MEASURES 
753 
9.1 
Primary Outcome Measures 
754 
The primary outcomes are changes in static and dynamic bone histomorphometry after 1 year, 2 years, 
755 
and 4 years of HPTH therapy. Those changes will be determined from antibiotic-labeled biopsies taken 
756 
before and during HPTH therapy. The static and dynamic bone histomorphometry variables that will be 
757 
assessed as primary outcomes are listed in the following:  
758 
1. 
Mineralized perimeter 
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PI name: Rachel I. Gafni 
 
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2. 
Bone formation rate 
760 
3. 
Cortical width 
761 
4. 
Cortical area 
762 
5. 
Osteoid width 
763 
6. 
Osteoid perimeter 
764 
7. 
Mineral apposition rate 
765 
9.2 
Secondary Outcome Measures 
766 
The secondary outcome measures are listed below: 
767 
1. 
Changes in bone mineralization density distribution will be assessed in bone biopsies by back-
768 
scattered electron imaging at 1, 2 and 4 years of HPTH therapy. The specific outcomes that will 
769 
be measured include: 
770 
a. 
spectral calcium-mean 
771 
b. 
calcium-peak 
772 
c. 
calcium-width 
773 
2. 
Non-biopsy outcomes are being measured every 6 months (annually for some outcomes) over 
774 
the 5 years of HPTH therapy. Changes from baseline in the following outcomes will be 
775 
assessed: 
776 
a. 
Biochemical markers of bone metabolism: osteocalcin, bone-specific alkaline phosphatase, 
777 
collagen cross-linked N-telopeptide.  
778 
b. 
Serum and urine calcium; 1,25-OH2-Vitamin D 
779 
c. 
Bone density assessed by DXA and quantitative CT 
780 
d. 
Nephrocalcinosis by ultrasound and CT 
781 
e. 
Fatigue Symptom Inventory 
782 
f. 
6-Minute Walk Test 
783 
g. 
SF-36 Health Survey 
784 
Where appropriate, biochemical and biopsy data will be compared to age, sex, and ethnicity-matched 
785 
controls. 
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PI name: Rachel I. Gafni 
 
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9.3 
Tertiary Outcome Measures 
787 
The tertiary outcomes are early changes in blood chemistries and FGF23, renal mineral handling, and 
788 
PTH sensitivity with the initiation of HPTH.  Tertiary outcome measures include: 
789 
a. Serum albumin, calcium, phosphorus, magnesium, sodium, potassium, chloride, Total CO2, 
790 
creatinine, glucose, urea nitrogen, and FGF23 
791 
b. Urine cAMP, creatinine, phosphorus, calcium, and pH 
792 
 
793 
10 STATISTICAL ANALYSIS 
794 
10.1 Analysis of Data/Study Outcomes 
795 
The overall analysis objective is to utilize exploratory and hypothesis testing methods to characterize the 
796 
response profile over time to HPTH therapy in the primary and secondary endpoints. The bone biopsy 
797 
measures are assessed at baseline and at 1, 2, and 4 years in 3 separate arms, while most other endpoints 
798 
are assessed every 6 months from baseline to 5 years of therapy. Thus, analyses of bone biopsy endpoints 
799 
involve both within-arm and between-arm comparisons at the 3 times, while all other analyses will utilize 
800 
standard repeated measures methods for longitudinal data. 
801 
These analyses will initially include all randomized subjects who remain evaluable for the endpoints, 
802 
including those eligible out of the subjects currently on conventional therapy plus the 36 newly enrolled 
803 
subjects. However, if covariate adjustment in analyses described below indicates that there are differences 
804 
between these strata, then the 3 strata will be analyzed separately. The subjects who were on HPTH under 
805 
the previous version of the protocol will be analyzed separately using similar analysis methods, 
806 
recognizing the limitations of the small sample size (≤ 8). Any subject who enters menopause prior to the 
807 
second bone biopsy will remain in the study and will undergo the second biopsy; however, the results will 
808 
be reported separately and not included in the data analyses of the randomized groups.  It is felt that 
809 
reviewing the results from a menopausal woman anecdotally may give insight into possible treatment 
810 
effects in a menopausal sub-population.  Data will be summarized graphically and in tabular form using 
811 
standard descriptive statistics for categorical and continuous measures, with appropriate consideration of 
812 
underlying distributional assumptions. All tests of significance will be two-tailed at the 0.05 level. 
813 
For the bone biopsy endpoints, paired t-tests will be used to test the hypotheses that the 1, 2, and 4-year 
814 
changes from baseline are significantly different from zero. One-way analysis of variance (ANOVA) will 
815 
be used to compare these differences to each other, with protected individual linear contrasts performed if 
816 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
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Version: 17.0 
 
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the overall F-test is significant. The effects of selected baseline covariates, including gender and 
817 
menopausal status, will be assessed using analysis of covariance (ANCOVA) in a sensitivity analysis. 
818 
Exploratory graphical methods will also be used to assess distributional assumptions and potential 
819 
differences in responses between the strata. Log-transformation of raw data or non-parametric test 
820 
alternatives may be considered if indicated by these exploratory analyses. 
821 
In the event that the 1, 2, and 4-year changes from baseline are not significantly different from each other 
822 
by ANOVA, we will consider pooling them using a paired t-test to test for significance of the pooled 
823 
changes from baseline, ignoring the follow-up time. This may be indicated if either the observed standard 
824 
deviation of the differences is larger than expected or if greater power is desired to test for an overall 
825 
smaller effect size. For example, with 24 subjects, there is 80% power to detect a change from baseline in 
826 
mineralizing perimeter of 4% if the standard deviation is 7%, as expected, but it is 9%, if the standard 
827 
deviation is as large as 15%, using a 0.05 level paired t-test. 
828 
Since there are a number of pre-specified reasons for discontinuing subjects from study (see Section 8) 
829 
and the dropout rate could be relatively high (33%), secondary sensitivity analyses may be performed on 
830 
the bone biopsy data if a large number of those discontinuations or dropouts occurs before the subject’s 
831 
second biopsy. For each such missing follow-up bone biopsy, the second biopsy endpoint value will be 
832 
imputed using different rules (e.g. baseline biopsy value, and mean, minimum or maximum of those 
833 
present) and the results of analyses of those data will be compared to the primary analysis on only 
834 
evaluable subjects to determine if there is evidence that dropouts may have biased the primary analysis 
835 
results. 
836 
All other endpoints are assessed repeatedly over the 5-year study period, and most are assessed every 6 
837 
months. This longitudinal multivariate data set will be analyzed using standard mixed models or 
838 
generalized estimating equations techniques to characterize the therapy response profile for each 
839 
endpoint. Patterns of missing data will be assessed and appropriate accommodations will be made in the 
840 
methods depending on the apparent mechanism for generating the missing data. Dimensional reduction 
841 
techniques may be employed with sets of related endpoints that are highly correlated. The objective will 
842 
be to produce a graphical and analytical profile of each physiological and behavioral response to therapy 
843 
over time. In addition, mixed model methods will be used to determine if patterns in selected secondary 
844 
endpoints over time are predictive of primary biopsy endpoints, in order to evaluate their potential use as 
845 
either surrogate biomarkers for bone histomorphometic measures or as classifiers that could be used to 
846 
identify subjects more responsive to HPTH treatment.  
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PI name: Rachel I. Gafni 
 
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Subjects and their data will be monitored closely throughout the study for safety; data will be submitted 
848 
regularly for DSMC review as described in Section 15.  In addition, preliminary analyses using methods 
849 
described above may be performed when all evaluable subjects meet certain early milestones, for 
850 
example, after all subjects have completed their one year biopsy. These analyses will be designed to 
851 
evaluate early changes from baseline in primary and secondary measures after one year of HPTH 
852 
treatment and to assess the predictive values of selected secondary measures in relation to the primary 
853 
endpoints.  
854 
10.2 Power Analysis 
855 
Sample size calculations were based on 2 of the primary bone biopsy outcome measures, cancellous bone 
856 
mineralizing perimeter and bone formation rate, using preliminary data from the 5 previously enrolled 
857 
subjects who had biopsies at baseline and at 1 year of HPTH therapy. For mineralizing perimeter, the 
858 
mean (standard deviation) of the 1-year changes from baseline was 22 (7) %, and for bone formation rate 
859 
it was 0.23 (0.07) μm2/mm/d. For design purposes, we assumed that a clinically meaningful change in 
860 
mineralizing perimeter from baseline to either 1, 2 or 4 years of therapy is 10% and will establish the 
861 
sample size required to detect a difference at least that large with adequate power. Using a two-tailed 0.05 
862 
level paired t-test, we found that 8 new subjects in each follow-up arm yielded 93% power to detect a 
863 
difference of 10% at any of the follow-up times. For bone formation rate, we assumed that a clinically 
864 
meaningful change from baseline is 0.10 μm2/mm/d, which corresponds to an identical standardized 
865 
minimum detectable effect size of 0.10/0.07=1.4 compared to 10/7=1.4 for mineralizing perimeter. As a 
866 
result, 8 new subjects per arm will also yield 93% power to detect significant paired differences in bone 
867 
formation rate of 0.10 μm2/mm/d.  
868 
A secondary analysis objective of the primary bone biopsy endpoints is to determine if there are 
869 
differences between the changes from baseline over time, using analysis of variance (ANOVA) for these 
870 
between-biopsy-arm comparisons. With 8 new subjects per arm, there is 75% power to detect a 
871 
significant difference in mineralizing perimeter with a two-tailed 0.05 level overall F-test if the 3 
872 
differences from baseline are, for example, 10%, 15% and 21%, assuming a within-group standard 
873 
deviation of 7%. Similar results were obtained for bone formation rate. 
874 
Finally, based on current experience, the dropout rate of subjects on HPTH therapy for 5 years could be as 
875 
high as 1 in 3 (33%). To account for that, 36 new eligible subjects will be randomized to the 3 biopsy 
876 
follow-up time arms, which should result in at least 24 new subjects being evaluable for the primary 
877 
analyses of the bone biopsy endpoints at years 1, 2 and 4. Up to 10 additional subjects may be screened 
878 
but not enter the treatment or randomization phase. 
879 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
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10.3 Randomization and Stratification 
880 
While there is only one treatment group, subjects will be randomized 1:1.2:1.4 at baseline to the 3 bone 
881 
biopsy follow-up times of 1, 2, or 4 years, respectively. Heavier weighting is given to the arms with 
882 
longer follow-up times as these arms are anticipated to have more dropouts. In addition, the 
883 
randomization will be stratified on 3 factors, gender (Male/Female), menopausal status (pre / post 
884 
menopausal), and prior participation in this trial (Yes/No). Stratification on gender is indicated because of 
885 
known gender-based differences in bone formation. Stratification on menopausal status is indicated 
886 
because of known hormonal changes that may influence bone mineralization. Stratification on prior 
887 
participation is indicated because the subjects enrolled under the previous version of the protocol will 
888 
have their pre-conventional therapy biopsy used as their baseline biopsy (new subjects will have their 
889 
baseline biopsy at the end of conventional therapy) and the effects of conventional therapy on the biopsies 
890 
is not known with certainty. In order to avoid potential loss of power in the primary analyses if these 3 
891 
strata are found to be different, 36 new subjects will be enrolled in one stratum and those eligible to 
892 
continue from among the 10 currently enrolled subjects will be enrolled in the other stratum. 
893 
Since the target subject sample size is relatively small and there are 3 binary stratification variables, a 
894 
dynamic allocation algorithm based on the Pocock-Simon method 27  will be used. This algorithm weights 
895 
the probabilities of assignment to the 3 arms for each subject so as to increase the probability the subject 
896 
will be assigned to the arm which will result in the least overall imbalance between the 3 groups with 
897 
respect to the distributions of the 3 stratification factors. Given dropouts during the enrollment period, the 
898 
algorithm will also consider any imbalances resulting from those dropouts occurring before their second 
899 
biopsy and will adaptively rebalance the 3 arms across the two stratification variables with prospectively 
900 
randomized subjects. The algorithm is transparently implemented within the web-based randomization 
901 
system when subjects are randomized at baseline. 
902 
11 HUMAN SUBJECTS PROTECTION 
903 
11.1 Subject Selection 
904 
Selection of subjects will not be limited by gender, race, or ethnicity.  However, as hypoparathyroidism in 
905 
adults most frequently occurs as a surgical complication of thyroid surgery for autoimmune thyroid 
906 
disease and/or thyroid cancer, conditions which occur more commonly in Caucasian women, a 
907 
disproportionate number of Caucasian women are expected to be enrolled in this protocol.  Men and 
908 
women over age 70 have been excluded to avoid the onset of senile osteoporosis as a confounding factor.   
909 
Because bone metabolism is altered during menopause and because this would confound the results of the 
910 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
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study, women who are likely to enter menopause during the study (those ages 46 – 52) will not be 
911 
enrolled.   
912 
11.2 Justification for Exclusion of Children 
913 
Children have been excluded from this trial because their rapid changes in growth and bone 
914 
mineralization would affect interpretation of the data and rhPTH is not recommended for use in children.  
915 
11.3 Justification for Exclusion of Other Vulnerable Subjects 
916 
PTH has not been studied for use in pregnancy, and bone metabolism is altered during pregnancy, 
917 
lactation. Therefore, pregnant and lactating women have been excluded.  
918 
11.4 Justification of Sensitive Procedures 
919 
Not applicable. 
920 
11.5 Safeguards for Vulnerable Populations 
921 
Verbal confirmation of contraception use will be obtained from women of child-bearing potential during 
922 
the history and a pregnancy test will be performed during screening and each inpatient NIH visit. 
923 
11.6 Qualifications of Investigators 
924 
The following investigators are licensed physicians who are board certified or board eligible in the 
925 
specialty of endocrinology and have expertise in treating patients with hypoparathyroidism.  They are 
926 
qualified to recruit and screen subjects, perform assessments, assess adverse events, order and interpret 
927 
tests, prescribe treatments including HPTH handle specimens, perform regulatory reporting/paperwork, 
928 
evaluate and interpret data. 
929 
x 
Rachel I. Gafni, MD (will obtain informed consent)  
930 
x Alison M. Boyce, MD (will not obtain informed consent) 
931 
x Michael T. Collins, MD (will obtain informed consent) 
932 
x 
Mary Scott Ramnitz, MD (will obtain informed consent) 
933 
The following investigator is a licensed physician with a specialty in endocrinology.  He has expert 
934 
training in bone densitometry. He will be responsible for performing and interpreting DXA scans. 
935 
x James C. Reynolds, MD  
936 


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The following investigators are licensed registered nurses with expertise in clinical research and treatment 
937 
of endocrine disorders.  They are qualified to recruit and screen subjects, perform assessments, assess 
938 
adverse events, order and interpret tests within the scope of their clinical credentials, administer 
939 
prescribed treatments including HPTH, handle specimens, perform regulatory reporting/paperwork, 
940 
evaluate and interpret data, and obtain informed consent.  
941 
x Beth Brillante, RN, MBA 
942 
x Lori Guthrie, RN 
943 
The following investigator is a board certified orthopedic surgeon who will perform iliac crest bone 
944 
biopsies.  She will also order and interpret tests, handle specimens, prescribe treatments, and evaluate and 
945 
interpret data. 
946 
x Laura L. Tosi, MD 
947 
The following investigator is board eligible in oral and maxillofacial surgery. This investigator will 
948 
perform assessments, perform bone biopsies, order medications, order tests, and interpret tests. 
949 
x 
Andrea Burke, MD, DMD 
950 
11.7 Qualifications of Non-NIH Collaborators 
951 
The following non-NIH collaborators are scientists with expertise in the study of bone specimens.  They 
952 
will perform analyses on iliac crest bone biopsies outside of NIH. 
953 
x Hua Zhou, MD 
954 
x David Dempster, PhD 
955 
x Klaus Klaushofer, MD 
956 
x Paul Roschger, PhD 
957 
The following non-NIH collaborator is a board-certified nephrologist.  This investigator will analyze data 
958 
and will not have access to patient identifying information. 
959 
x Craig Langman, MD 
960 
12 ANTICIPATED BENEFIT 
961 
It is anticipated that participants in this study will benefit directly from their treatments with conventional 
962 
therapy and may benefit from therapy with the investigational drug, HPTH. As described in Section 4.5, 
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subjects will be monitored throughout the study period in order to optimize the effects of conventional 
964 
and investigational treatments on their calcium metabolism. 
965 
13 CLASSIFICATION OF RISK 
966 
13.1 Adults 
967 
This study is classified as research involving more than minimal risk. This risk is justified as the current 
968 
treatment is inadequate and associated with morbidity. 
969 
13.2 Overall Risk and Benefit Consideration 
970 
Risks of the study are reasonable in relation to the anticipated benefit. 
971 
14 CONSENT DOCUMENTS AND PROCESS 
972 
14.1 Designation of Those Obtaining Consent 
973 
Informed consent will be obtained by study investigators as designated in Section 11.6. 
974 
14.2 Consent Procedures 
975 
All subjects (or their legally authorized representative) will be required to sign and date a consent form 
976 
before participating in any portion of the study. Subjects previously enrolled in this protocol will be re-
977 
consented at their first study visit, as described in Sections 4.5.1-4.5.3. All participants will receive a 
978 
verbal explanation in terms used to their comprehension of the purposes, procedures, and potential risks 
979 
of the study and their rights as research participants.  Participants will also have the opportunity to 
980 
carefully review the written consent form and ask questions regarding this study prior to signing.  A copy 
981 
of the informed consent will be given to the prospective subject for review, and the principal investigator 
982 
or an associate investigator, will review the consent form with the subject. In the presence of a witness, 
983 
the investigator will request the subject’s signature, indicating consent. The subject will be informed that 
984 
participation is voluntary and that he/she may withdraw from the study at any time, for any reason.  
985 
14.3 Consent Documents 
986 
The consent document captures all required elements, including the purposes, procedures, benefits, and 
987 
potential risks of the study (see Section 25).  The consent process will be documented in the subjects’ 
988 
medical records. The documentation of the consent process will include the following elements: 
989 
x Date and time of consent  
990 
x Topics discussed with the subject (e.g. risk, benefits, alternatives) 
991 


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x Confirmation that subject had adequate time to review the consent, that the subject’s questions 
992 
were answered, and that a copy of the consent was provided to the subject 
993 
The consent forms will be updated or revised whenever important new safety information is available, 
994 
whenever the protocol is amended, or whenever any new information becomes available that may affect 
995 
participation in the study. The original forms will become part of the permanent medical record and 
996 
copies will be provided to the subjects.  
997 
15 DATA AND SAFETY MONITORING 
998 
15.1 Data and Safety Monitor 
999 
The principal investigator will be responsible for monitoring the data and accruing safety information.  
1000 
Serious adverse event (SAE) monitoring will be supported by an independent medical monitor and 
1001 
support team from the Clinical Research Operations and Management Support (CROMS) at Rho.  
1002 
Clinical monitoring for this study will be done by CROMS at Rho in collaboration with the NICDR 
1003 
Clinical Director and Principal Investigator.  
1004 
The NIDCR Division of Intramural Research Data and Safety Monitoring Committee (DSMC) will 
1005 
provide data and safety review and recommendations to the NIDCR Clinical Director for the study.  The 
1006 
DSMC will include members with expertise in a broad range of areas, including human subjects’ 
1007 
protection, research ethics, clinical trial implementation, biostatistics, and medical bone and mineral 
1008 
metabolism.  
1009 
15.2 
4BData and Safety Monitoring Plan 
1010 
Data and safety will be monitored by the Principal Investigator along with the NIDCR Clinical Director 
1011 
and the independent medical monitor from CROMS.    
1012 
The PI is responsible for monitoring the study progress and study data. The PI will also maintain 
1013 
responsibility for ensuring the accuracy, completeness, timeliness, and legibility of the data. The PI and 
1014 
associate investigators are also required to keep accurate and timely records to ensure that the conduct of 
1015 
the study is fully documented. The PI will review individual study subject data upon each patient 
1016 
encounter; she will review aggregate data reports on monthly basis to review enrollment progress and 
1017 
adverse events. Trends will be discussed with the protocol team to ensure subject safety, study 
1018 
compliance and recruitment goals are met. 
1019 
Safety monitoring for this study will be the responsibility of the PI and supported by CROMS. The 
1020 
CROMS independent medical monitor will review serious adverse events that are reported to CROMS. 
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The CROMS medical monitor will review the SAE report, request additional information about the event 
1022 
if necessary and provide a medical monitor assessment within 2 business days of receipt of the SAE 
1023 
report.  The investigator and independent medical monitor may discuss specific events or trends if noted. 
1024 
The investigator will determine the appropriate clinical action for the subject. 
1025 
The DSMC will review data approximately  annually related to enrollment progress, trial implementation, 
1026 
subject safety, and clinical efficacy. The DSMC will also consider current information from other sources 
1027 
on the biology of the disease, the investigational product, and the patient population under study. Based 
1028 
on these reviews, the DSMC will make recommendations to the NIDCR Clinical Director concerning the 
1029 
continuation, modification, or termination of the trial. The NIDCR Clinical Director determines which 
1030 
recommendations from the DSMC will be accepted and required of the principal investigator to address.  
1031 
The roles and responsibilities of committee members and meeting procedures will be formally described 
1032 
in a charter.  
1033 
The DSMC and the investigator will review the semi-annual DSMC reports to determine whether the 
1034 
aggregate safety data should be reported to the FDA in an expedited manner.   
1035 
Aggregate data will be reported in an expedited manner to the FDA if the DSMC or the investigator 
1036 
believes those data represent an unexpected set of related SAEs for which there is a reasonable possibility 
1037 
that they were caused by the study product (see Appendix 24.1 for a definition of expectedness). 
1038 
See Section 17 for a description of expedited FDA, IND reports of individual SAEs. 
1039 
15.3 Criteria for Stopping the Study or Suspending Enrollment or Procedures 
1040 
The study will be temporarily halted for any of the following reasons:  
1041 
x A fatal or life-threatening event (including osteosarcoma) assessed as related to use of the 
1042 
investigational product  
1043 
x Two or more similar grade 3 AEs/SAEs that are permanent or not easily reversible and assessed 
1044 
as related to the use of the investigational product. Easily reversible is defined as responding to 
1045 
treatment or dose titration such that the severity grade of the AE is reduced to 1 or 2.   
1046 
x Five or more treatment failures, defined as significant deterioration in metabolic control on PTH 
1047 
as defined by repeated measurements of serum calcium < 7 mg/dL for more than 4 weeks.  
1048 
The principal investigator will be responsible for monitoring accruing safety data related to stopping 
1049 
criteria and for notifying the DSMC chair when a halting rule is met. The DSMC Chair will be informed 
1050 


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Date:  September 9, 2015 
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Version: 17.0 
 
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by email within 1 business day that a halting rule has been reached and confirmed. When a halting rule is 
1051 
met, enrollment will be temporarily suspended while the DSMC considers the data.   During this hold 
1052 
period, ongoing subjects will continue to receive HPTH and conventional care for hypoparathyroidism 
1053 
and will continue to be followed for clinical and safety outcomes.  The DSMC will assemble an 
1054 
emergency meeting within one month of being notified that a study halting criterion has been met. Prior 
1055 
to the receipt of the DSMC decision, the study team will actively manage the subject(s) who triggered the 
1056 
alert by both treating the AE and titrating the dose, as clinically appropriate.  The DSMC will issue a 
1057 
recommendation on study continuation to the NIDCR Clinical Director after reviewing data related to the 
1058 
halting rule. If NIDCR leadership terminates the study based on DSMC recommendations, subjects will 
1059 
be weaned off study drug and transitioned to conventional therapy. The principal investigator and the 
1060 
clinical director will provide the recommendations of the DSMC to the IRB.  
1061 
15.4 Data and Safety Monitoring Committee Oversight 
1062 
The NIDCR Data and Safety Monitoring Committee (DSMC) will have oversight responsibilities for the 
1063 
study. The committee will include members with expertise in a broad range of areas, including human 
1064 
subjects protection, research ethics, clinical trial implementation, biostatistics, and medical bone and 
1065 
mineral metabolism. In addition to any safety alerts, as defined in Section 15.3, the DSMC will review 
1066 
data approximately once a year related to enrollment progress, trial implementation, subject safety 
1067 
(including BMD), and clinical efficacy. The DSMC will also consider current information from other 
1068 
sources on the biology of the disease, the investigational product, and the patient population under study. 
1069 
Based on these reviews, the DSMC will make recommendations to the principal investigator and the 
1070 
NIDCR clinical director concerning the continuation, modification, or termination of the trial. The roles 
1071 
and responsibilities of committee members and meeting procedures will be formally described in a 
1072 
charter.  
1073 
The DSMC and the investigator will review the annual DSMC reports to determine whether the aggregate 
1074 
safety data should be reported to the FDA in an expedited manner.   
1075 
Aggregate data will be reported in an expedited manner to the FDA if the DSMC or the investigator 
1076 
believes those data represent an unexpected set of related SAEs for which there is a reasonable possibility 
1077 
that they were caused by the study drug (see Appendix 24.1 for a definition of expectedness). 
1078 
See Section 17 for a description of expedited IND reports of individual SAEs. 
1079 
 
1080 


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16 QUALITY ASSURANCE 
1081 
16.1 Quality Assurance Monitor 
1082 
The NIDCR Office of Clinical Trials Operations and Management (OCTOM) is responsible for ensuring 
1083 
an appropriate clinical monitoring plan is developed that is specific for this study and data management 
1084 
system.  Clinical site monitoring will be coordinated with the NIDCR Clinical Director and the Principal 
1085 
Investigator.  OCTOM and its designee, CROMS, will conduct clinical monitoring according the clinical 
1086 
monitoring plan and will provide a report of monitoring findings associated with each visit.  
1087 
16.2 Quality Assurance Plan 
1088 
Clinical monitoring for this study is based on a Clinical Monitoring Plan that was developed by CROMS 
1089 
in collaboration with the National Institute of Dental and Craniofacial Research (NIDCR), Office of 
1090 
Clinical Trials Operations and Management (OCTOM) project officer and the NIDCR Clinical Director. 
1091 
The purpose of the clinical monitoring activities is to ensure that the rights of human subjects are 
1092 
protected, that the study is implemented in accordance with the protocol, and that the integrity of study 
1093 
data is maintained. The plan specifies the frequency, procedures, and levels of monitoring activities. 
1094 
Some monitoring activities will be performed remotely (e.g. review of regulatory documents), while 
1095 
others will take place on site (e.g. verification of study databases against source documentation, review of 
1096 
consent documentation, study drug administration). Staff from CROMS will provide a final site visit 
1097 
report to the principal investigator in approximately 21 calendar days from the last day of the visit. The 
1098 
frequency of other reports based on other monitoring activities will be specified in the monitoring plan. 
1099 
Monitoring activities will include a study initiation visit prior to study start-up, interim site monitoring 
1100 
visits, a close-out visit and, if necessary, for-cause visits. Interim monitoring visits will take place at least 
1101 
annually and based on rate of accrual. During interim monitoring visits, the clinical research associate 
1102 
will complete a review of subject medical and research records, electronic case report forms, consent 
1103 
documents, unanticipated problems, adverse events, site regulatory documents, etc. Final monitoring visit 
1104 
reports will be provided to the PI, NIDCR Clinical Director, and OCTOM after monitoring visit 
1105 
completion.  
1106 
The components of the data quality control and assurance program are 1) real-time detection and 
1107 
correction of errors within the EDC system, 2) verification of key outcome measurements during clinical 
1108 
monitoring visits, and 3) periodic data review by CROMS. At the time of data entry, the EDC system 
1109 
alerts the user to missing, out-of-range, and inconsistent values and provides the user the opportunity to 
1110 
correct errors in real time. In accordance with federal regulations, the system records all elements of data 
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entry (i.e., time, date, verbatim text, and the name of the person performing the data entry). During 
1112 
periodic clinical monitoring visits, monitors will verify key outcome measurements by comparing data in 
1113 
the EDC system to source documentation. The frequency of monitoring visits and the number of records 
1114 
and data fields monitored are described in the study Clinical Monitoring Plan (CMP). Data managers at 
1115 
CROMS will generate periodic summary reports for the study staff to review. 
1116 
Data fields in the EDC that are the initial source of the data record (i.e. no source documentation is 
1117 
maintained) include those captured in the telephone prescreening (yes/no qualification information only). 
1118 
17 UNANTICIPATED PROBLEM,  ADVERSE EVENT,  AND PROTOCOL 
1119 
DEVIATION REPORTING 
1120 
The Principal Investigator is responsible for detecting, documenting, and reporting unanticipated 
1121 
problems (UPs),  adverse events (AEs), including serious adverse events (SAEs), and protocol deviations 
1122 
in accordance with the protocol, IRB requirements, NIH Policy, and federal regulations. Definitions and 
1123 
additional reporting guidelines are provided in NIH SOP 16.  Relatedness to the research of all serious 
1124 
adverse events will be determined by the PI in consultation with the Clinical Director’s office.   
1125 
Definitions of the different types and characteristics of safety events, protocol deviations, and additional 
1126 
reporting guidelines are provided in Appendix 24.1.   In the event of a discrepancy, NIH SOP 16 will be 
1127 
the prevailing document. 
1128 
Serious unanticipated problems and serious protocol deviations will be reported to the IRB and CD as 
1129 
soon as possible and in writing on the Problem Report Form no more than 7 days after the PI first learns 
1130 
of the event.  Non- serious unanticipated problems and non -serious protocol deviations will be reported 
1131 
to the IRB and Clinical Director as soon as possible and in writing on the Problem Report Form not more 
1132 
than 14 days after the PI first learns of the event.  
1133 
Deaths will be reported to the Clinical Director as soon as possible, but not more than 7 days after the PI 
1134 
first learns of the event. 
1135 
All UPs, adverse events, and protocol deviations will be summarized and reported to the IRB at the time 
1136 
of continuing review with the following exceptions: hospitalizations for elective procedures or surgeries, 
1137 
hospitalizations for psychosocial or convenience reasons will not be reported.  In this population, 
1138 
symptoms of hypocalcemia (a comorbidity of hypoparathyroidism), such as numbness, cramping, and 
1139 
fatigue are characteristic of the underlying disorder and may be present continually. Kidney stones may 
1140 
be as frequent as several times a year in the study population.  Therefore, these incidents and the 
1141 
hospitalizations mentioned above will not be reported at the time of continuing review unless they occur 
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at a greater severity or frequency than expected.   Adverse events occurring at a greater severity or 
1143 
frequency than expected will be reported as Unanticipated Problems as delineated above.    
1144 
SAEs that are unexpected and for which there is a reasonable possibility that they are related to the use of 
1145 
the investigational product will be reported to the FDA in an expedited manner. If the event is also life-
1146 
threatening or results in death, the FDA will be notified of the event no later than 7 calendar days after the 
1147 
investigator becomes aware of the event. All other qualifying SAEs will be reported to the FDA within 15 
1148 
calendar days. All adverse events, including other non-expedited serious adverse events will be reported 
1149 
to the FDA at least annually in a summary format. 
1150 
17.1 Pregnancy Reporting and Follow-Up 
1151 
Pregnancies will be recorded from the time written informed consent is obtained until the subject is 
1152 
withdrawn from the study. Results of all pregnancy tests will be given to the subject and/or legally 
1153 
authorized representative, as appropriate. Subjects who become pregnant during the study will be weaned 
1154 
off of PTH and will be followed until a pregnancy outcome is reached at which time they will be 
1155 
withdrawn from the safety follow-up portion of the study.  The subjects will be referred to a physician 
1156 
outside of NIH for care.  If the pregnancy results in anything other than a normal birth or elective abortion 
1157 
of a healthy fetus, it will be reported as an SAE. At the end of the pregnancy follow-up period, the 
1158 
subjects will be withdrawn from the trial.  
1159 
18 ALTERNATIVES TO PARTICIPATION OR ALTERNATIVE THERAPIES 
1160 
Alternative to participation is use of current standard-of-care therapy for hypoparathyroidism: oral 
1161 
calcium and vitamin D analogues. There are no PTH preparations that are FDA-approved for the 
1162 
treatment of hypoparathyroidism. Subjects may be eligible for participation in other clinical trials 
1163 
evaluating treatment for hypoparathyroidism or patients may be able to convince their personal physicians 
1164 
to prescribe PTH off-label 
1165 
19 CONFIDENTIALITY 
1166 
19.1 Research Data and Investigator Medical Records 
1167 
A subject’s privacy and confidentiality will be respected throughout the study. Each subject will be 
1168 
assigned a code number. That number, rather than the participant’s name, will be used on CRFs, the study 
1169 
database, and on samples collected for research (see Section 5).  Individual research charts, which contain 
1170 
the link between the subject’s name and code, will be kept in locked cabinets or rooms, and computer 
1171 
research databases will be on computer networks that are password protected and encrypted. 
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19.2 Stored Samples 
1173 
All samples are coded and do not have personal identifiers. The codes for identifiers are contained in a 
1174 
subject code log that is maintained in secure research files.  The key (i.e. list) that links each subject’s 
1175 
name to his/her code will be stored in secured computer files.  Only study investigators and their 
1176 
delegates, such as the study staff, laboratory staff, and the DCC, will have access to the study samples or 
1177 
data. 
1178 
19.3 Special Precautions 
1179 
Access to study data will be restricted as described above.  The study PI, Associate Investigators, and 
1180 
NIDCR Site personnel will have access to research records, study data and research samples.  Clinical 
1181 
Research Operations and Management Support and OCTOM will be able to access study data.  Clinical 
1182 
Research Associates from CROMS will also have access to research records for monitoring purposes 
1183 
only.  A summary of study results will be available on http://www.ClinicalTrials.gov, as required by U.S. 
1184 
Law.  
1185 
20 CONFLICT OF INTEREST / TECHNOLOGY TRANSFER 
1186 
20.1 Distribution of NIH Guidelines 
1187 
NIH guidelines on conflict of interest have been distributed to all investigators. The principal investigator 
1188 
is responsible for ensuring that NIH policies and guidelines are followed.  
1189 
20.2 Conflict of Interest 
1190 
There are no conflicts of interest to report. 
1191 
20.3 Role of a Commercial Company or Sponsor 
1192 
Not applicable. 
1193 
21 TECHONOLOGY TRANSFER 
1194 
A material transfer agreement exists between NIH and David Dempster (via Helen Hayes Hospital) and 
1195 
Klaus Klaushofer (via Ludwig Boltzmann Institute of Osteology) who will be analyzing the bone biopsy 
1196 
specimens. 
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22 RESEARCH AND TRAVEL COMPENSATION 
1198 
There will be no financial compensation for participating in the study; however, travel/subsistence 
1199 
expenses and research-related co-pays will be reimbursed according to the NIH policy established 
1200 
January 5, 2009. 
1201 
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23 REFERENCES 
1203 
1. 
Marx SJ. Hyperparathyroid and hypoparathyroid disorders. N Engl J Med 2000;343:1863-75. 
1204 
2. 
Winer KK, Yanovski JA, Cutler GB, Jr. Synthetic human parathyroid hormone 1-34 vs calcitriol 
1205 
and calcium in the treatment of hypoparathyroidism. Jama 1996;276:631-6. 
1206 
3. 
Winer KK, Yanovski JA, Sarani B, Cutler GB, Jr. A randomized, cross-over trial of once-daily 
1207 
versus twice-daily parathyroid hormone 1-34 in treatment of hypoparathyroidism. J Clin Endocrinol 
1208 
Metab 1998;83:3480-6. 
1209 
4. 
Winer KK, Sinaii N, Peterson D, Sainz B, Jr., Cutler GB, Jr. Effects of once versus twice-daily 
1210 
parathyroid hormone 1-34 therapy in children with hypoparathyroidism. J Clin Endocrinol Metab 
1211 
2008;93:3389-95. 
1212 
5. 
Winer KK, Ko CW, Reynolds JC, et al. Long-term treatment of hypoparathyroidism: a 
1213 
randomized controlled study comparing parathyroid hormone-(1-34) versus calcitriol and calcium. J Clin 
1214 
Endocrinol Metab 2003;88:4214-20. 
1215 
6. 
Abugassa S, Nordenstrom J, Eriksson S, Sjoden G. Bone mineral density in patients with chronic 
1216 
hypoparathyroidism. J Clin Endocrinol Metab 1993;76:1617-21. 
1217 
7. 
Langdahl BL, Mortensen L, Vesterby A, Eriksen EF, Charles P. Bone histomorphometry in 
1218 
hypoparathyroid patients treated with vitamin D. Bone 1996;18:103-8. 
1219 
8. 
Rubin MR, Dempster DW, Zhou H, et al. Dynamic and structural properties of the skeleton in 
1220 
hypoparathyroidism. J Bone Miner Res 2008;23:2018-24. 
1221 
9. 
Theman TA, Collins MT, Dempster DW, et al. PTH(1-34) replacement therapy in a child with 
1222 
hypoparathyroidism caused by a sporadic calcium receptor mutation. J Bone Miner Res 2009;24:964-73. 
1223 
10. 
Rubin MR, Sliney J, Jr., McMahon DJ, Silverberg SJ, Bilezikian JP. Therapy of 
1224 
hypoparathyroidism with intact parathyroid hormone. Osteoporos Int 2010;21:1927-34. 
1225 
11. 
Rubin MR, Dempster DW, Sliney J, Jr., et al. PTH(1-84) administration reverses abnormal bone-
1226 
remodeling dynamics and structure in hypoparathyroidism. J Bone Miner Res 2011;26:2727-36. 
1227 
12. 
Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and 
1228 
bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. 
1229 


PI name: Rachel I. Gafni 
 
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Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 53 of 55 
 
13. 
Hodsman AB, Bauer DC, Dempster DW, et al. Parathyroid hormone and teriparatide for the 
1230 
treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 
1231 
2005;26:688-703. 
1232 
14. 
Dempster DW, Cosman F, Kurland ES, et al. Effects of daily treatment with parathyroid hormone 
1233 
on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study. J Bone Miner 
1234 
Res 2001;16:1846-53. 
1235 
15. 
Levey AS, Stevens LA, Schmid CH, et al. A new equation to estimate glomerular filtration rate. 
1236 
Ann Intern Med 2009;150:604-12. 
1237 
16. 
Tregear GW, van Rietschoten J, Greene E, et al. Solid-phase synthesis of the biologically active 
1238 
N-terminal 1 - 34 peptide of human parathyroid hormone. Hoppe Seylers Z Physiol Chem 1974;355:415-
1239 
21. 
1240 
17. 
Kent GN, Loveridge N, Reeve J, Zanelli JM. Pharmacokinetics of synthetic human parathyroid 
1241 
hormone 1-34 in man measured by cytochemical bioassay and radioimmunoassay. Clin Sci (Lond) 
1242 
1985;68:171-7. 
1243 
18. 
Lilly E. Forteo, teriparatide (rDNA origin) injection, Package insert. Indianapolis; 2009. 
1244 
19. 
Lindsay R, Nieves J, Henneman E, Shen V, Cosman F. Subcutaneous administration of the 
1245 
amino-terminal fragment of human parathyroid hormone-(1-34): kinetics and biochemical response in 
1246 
estrogenized osteoporotic patients. J Clin Endocrinol Metab 1993;77:1535-9. 
1247 
20. 
Slovik DM, Neer RM, Potts JT, Jr. Short-term effects of synthetic human parathyroid hormone-
1248 
(1--34) administration on bone mineral metabolism in osteoporotic patients. J Clin Invest 1981;68:1261-
1249 
71. 
1250 
21. 
Tashjian AH, Jr., Goltzman D. On the interpretation of rat carcinogenicity studies for human 
1251 
PTH(1-34) and human PTH(1-84). J Bone Miner Res 2008;23:803-11. 
1252 
22. 
Vahle JL, Zuehlke U, Schmidt A, Westmore M, Chen P, Sato M. Lack of bone neoplasms and 
1253 
persistence of bone efficacy in cynomolgus macaques after long-term treatment with teriparatide 
1254 
[rhPTH(1-34)]. J Bone Miner Res 2008;23:2033-9. 
1255 
23. 
Harper KD, Krege JH, Marcus R, Mitlak BH. Osteosarcoma and teriparatide? J Bone Miner Res 
1256 
2007;22:334. 
1257 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 54 of 55 
 
24. 
Subbiah V, Madsen VS, Raymond AK, Benjamin RS, Ludwig JA. Of mice and men: divergent 
1258 
risks of teriparatide-induced osteosarcoma. Osteoporos Int 2009. 
1259 
25. 
Gafni RI, Brahim JS, Andreopoulou P, et al. Daily parathyroid hormone 1-34 replacement 
1260 
therapy for hypoparathyroidism induces marked changes in bone turnover and structure. J Bone Miner 
1261 
Res 2012;27:1811-20. 
1262 
26. 
Sikjaer T, Rejnmark L, Thomsen JS, et al. Changes in 3-dimensional bone structure indices in 
1263 
hypoparathyroid patients treated with PTH(1-84): a randomized controlled study. J Bone Miner Res 
1264 
2012;27:781-8. 
1265 
27. 
Pocock SJ, Simon R. Sequential treatment assignment with balancing for prognostic factors in the 
1266 
controlled clinical trial. Biometrics 1975;31:103-15. 
1267 
1268 


PI name: Rachel I. Gafni 
 
Date:  September 9, 2015 
Protocol number: 07-D-0016 
Version: 17.0 
 
Based on CNS IRB Protocol Template (rev 9.21.11) 
Page 55 of 55 
 
24 APPENDICES 
1269 
24.1 
Adverse Event and Unanticipated Problem, and Protocol Deviation 
1270 
Definitions, Characteristics and Additional Reporting Details 
1271 
24.2 
Pre-Screening Questionnaire and Eligibility Checklist 
1272 
24.3 
Study Schema 
1273 
24.4 
Schedule of Events 
1274 
24.5 
Calcium Questionnaire 
1275 
24.6 
DNA Consent Documents 
1276 
24.7 
SF-36 Survey 
1277 
24.8 
Fatigue Symptom Inventory 
1278 
24.9 
6-Minute Walk Test 
1279 
24.10 
Dosing Algorithm 
1280 
24.11 
Discharge Instructions 
1281 
24.12 
Bone Labeling Instructions 
1282 
24.13 
Forteo Package Insert 
1283 
24.14 
Study Blood Draw Amounts 
1284 
25 CONSENT FORMS 
1285 
Consent forms are attached. 
1286 


Protocol 07-D-0016
Effects of PTH replacement on Bone in Hypoparathyroidism
Appendices
Page
24.1 Adverse Event and Unanticipated Problem Definitions, Characteristics and 
Reporting Details............................................................................................. 2 
24.2
Pre-Screening Questionnaire and Eligibility Checklist................................. 10
24.3
Study Schema ................................................................................................ 17 
24.4
Schedule of Events ........................................................................................ 19 
24.5
Calcium Questionnaire .................................................................................. 23 
24.6
DNA Consent Documents ............................................................................. 25 
24.7
SF-36 Survey ................................................................................................. 30
24.8
Fatigue Symptom Inventory.......................................................................... 36 
24.9 6-Minute Walk Test....................................................................................... 45 
24.10 Dosing Algorithm.......................................................................................... 49 
24.11 Discharge Instructions ................................................................................... 51 
24.12 Bone Labeling Instructions............................................................................ 53 
24.13 Forteo Package Insert..................................................................................... 56 
24.14 Blood Draw Amounts ....................................................................................71
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Page 1 of 72


24.1 Adverse Event and Unanticipated 
Problem Definitions, Characteristics and 
Reporting Details 
Version Date 20-Dec-2013
Page 2 of 72


Adverse Event, Unanticipated Problem, & Protocol Deviation Definitions, Characteristics, 
& Additional Reporting Details
Protocol Number 07-D-00161
1
DEFINITIONS
1.1
Adverse Event
An AE is any untoward medical occurrence in a human subject, including any abnormal sign (for 
example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in research, whether or not considered related to the 
subject’s participation in the research. In the context of FDA reporting, an AE means any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related.  
1.2
Serious Adverse Event (SAE)
A Serious Adverse Event is defined as any adverse event that:
x Results in death
x Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred)
x Results in inpatient hospitalization or prolongation of an existing hospitalization  
x Results in persistent or significant disability/incapacity Results in congenital anomaly/ 
birth defect OR
x Based upon appropriate medical judgment, may jeopardize the subject’s health and may 
require medical or surgical intervention to prevent one of the other outcomes listed in this 
definition (examples of such events include allergic bronchospasm requiring intensive 
treatment in the emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug abuse). 
1 All AE, SAE, UP, and PD definitions are based on NIH HRPP Standard Operating Procedure #16, v 1, entitled 
“Reporting Requirements for Unanticipated Problems, Adverse Events, and Protocol Deviations.” Likewise, all 
event reporting described in the protocol and this Appendix complies with SOP #16.  Additional text has been 
included to clarify the concepts of expectedness and relatedness as they are differentially used by the NIH, for 
purposes of unanticipated problem reporting, and by the FDA, for purposes of SAE reporting. 
Version Date 20-Dec-2013
Page 3 of 72


1.3
Unanticipated Problem
The Office for Human Research Protections considers unanticipated problems to be any incident, 
experience, or outcome that meets all of the following criteria:
x
Is unexpected in terms of nature, severity, or frequency given a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent, and b) the characteristics 
of the subject population being studied; 
x
Is related or possibly related to participation in the research (possibly related means there 
is a reasonable possibility that the incident, experience, or outcome may have been 
caused by the procedures involved in the research); and 
x
Suggests that the research places subjects or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or 
recognized.
Expected adverse events may become unanticipated problems if they occur at a greater 
frequency or severity than was previously expected for an individual subject, as detailed in 
Section 17 of the protocol. 
An incident, experience, or outcome that meets the 3 criteria above will generally warrant 
consideration of substantive changes in order to protect the safety, welfare, or rights of subjects 
or others. Examples of corrective actions or substantive changes that might need to be considered 
in response to an unanticipated problem include the following: 
x
Changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects.
x
Modification of inclusion or exclusion criteria to mitigate the newly identified risks.
x
Implementation of additional procedures for monitoring subjects. 
x
Suspension of enrollment of new subjects. 
x
Suspension of research procedures in currently enrolled subjects.
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x
Modification of informed consent documents to include a description of newly 
recognized risks.
x
Provision of additional information about newly recognized risks to previously enrolled 
subjects.
Per the definition, only a subset of AEs would be further characterized as unanticipated 
problems. Additionally, there are other sorts of events that, while not AEs, would also be 
characterized as unanticipated problems (e.g., contaminated investigational product).
1.4
Protocol Deviation 
The Office of Human Subjects Research Protection defines a protocol deviation as any 
change, divergence, or departure from the IRB approved research protocol. 
A serious protocol deviation is a deviation that “meets the definition of a serious adverse 
event or if it compromises the safety, welfare, or rights of subjects or others.” More 
specifically, a deviation is serious if it meets any of the following criteria: 
x
Has harmed or poses a significant or substantive risk of harm to the research 
subject
x
Compromises the scientific integrity of the data collected for the study
x
Is a breach of human subject protection regulations, or NIH policies or procedures 
x
Involves serious or continuing non-compliance with applicable federal, state, local 
or institutional human subject protection laws, regulations, or policies, or 
procedures 
x
Is inconsistent with the NIH Human Research Protection Program’s research, 
medical, and ethical principles.
Protocol deviations will be reported to the IRB and NIDCR Clinical Director as described 
in protocol Section 15.5. 
2
EVENT CHARACTERISTICS 
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2.1
Severity of AE/SAEs
The severity of AE/SAEs will be graded according to the National Cancer Institute’s 
Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. The CTCAE 
provides a standard framework for recording, analyzing, and reporting events. Following 
CTCAE convention, AE/SAEs will be graded on a 5-point scale. If the severity of an event 
cannot be graded using CTCAE convention, the following guidelines will be used: 
1.
Mild: no intervention required 
2.
Moderate: minimal, local, or noninvasive intervention 
3.
Severe: significant symptoms requiring invasive intervention  
4.
Life-threatening: need for intensive care or emergent invasive procedure 
5.
Death: resulting from an adverse event
2.2
Relationship to the Investigational Product 
For all AEs, the investigator will determine the degree to which an event may have been caused 
by the investigational product.  “Relationship to the investigational product” is a factor used to 
guide SAE reporting to FDA.  The investigator’s assessment will be based on clinical judgment 
and information available in the study and investigational product documentation (e.g., Risks 
section of the protocol, Investigator’s Brochure or Drug Fact Sheet). Alternative causes such as 
natural history of the underlying disease, concurrent illness, concomitant therapy, study-related 
procedures, accidents, and other external factors will also be considered and investigated. The 
following guidelines will be used to aid this determination: 
1.
Related (Possible, probable, definite) 
a. The event is not commonly associated with hypoparathyroidism or with one of the 
study procedures 
b. The event is known to occur with administration of the product or similar 
products 
c. There is a temporal relationship between product administration and event onset 
d. The event abates when the investigational product is discontinued 
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Page 6 of 72


e. The event reappears upon a re-challenge with the product 
2.
Not Related (Not related, Unlikely)
a. The event is commonly associated with hypoparathyroidism or with one of the 
study procedures 
b. There is no temporal relationship between product administration and event onset 
c. An alternate etiology has been established
2.3
Relationship to the Research
For all AEs, the investigator will determine the degree to which an event may have been caused 
by participation in the research.  “Relationship to the research” is a factor used to identify 
unanticipated problems.  An event would be considered related to the research if the investigator 
believes that it may have been caused by the investigational product, by a study procedure, by 
another study assessment, or any other aspect of study participation.  
Relationship to the research will also partly determine whether a non-AE event might be 
qualified as an unanticipated problem.   
2.4
Expected, Based on the Investigational Product 
Serious adverse events that are considered to be at least possibly related to investigational 
product will be evaluated for expectedness based on the investigational product.  For purposes of 
reporting, the Principal Investigator will be responsible for determining whether SAEs are 
expected or unexpected based on safety information in the Investigator’s Brochure (or Drug Fact 
Sheet) and the protocol. An SAE will be considered unexpected if the specificity or severity is 
not described in the available safety information for the investigational product, published 
medical literature, the protocol, or the informed consent document.  
2.5
Expected, Based on the Study
Potential unanticipated problems (i.e., AEs or other events related to participation in the research 
that potentially place the subject at greater risk of harm) will be evaluated by the principal 
investigator to determine whether they were expected, based on the study.  This broad definition 
includes documented risks of HPTH and study procedures and assessments; it also includes 
Version Date 20-Dec-2013
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consideration of the nature of the subject population being studied.  Events that are expected 
based on any or all of these considerations are considered to be expected, based on the study.  
Such events would therefore not be considered UPs, because they would not satisfy the 
unexpectedness criterion.   
3
RECORDING AND REPORTING DETAILS
3.1
All Adverse Events
All AE/SAEs will be recorded from the time written informed consent is obtained until subject 
withdrawal (for non-treated subjects) and through the conclusion of the HPTH post-stabilization 
phase (for HPTH treated subjects).  
At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the last 
visit. The principal investigator will also review all source documentation related to inpatient 
study procedures for evidence of AEs. If subjects exhibit medical symptoms or conditions 
outside of the purview of the study (e.g., depression), they will be referred to their primary care 
provider or other appropriate medical personnel. Events will be followed until they return to 
baseline or until stabilization of the event. Participants who have AEs that are ongoing at the 
time their study participation ends will be referred to physicians outside of the NIH for care and 
follow-up. 
All AE/SAEs will be captured in CRFs that document the event term, severity, duration, 
relationship to use of the investigational product, relationship to the research, actions taken in 
response to the event, and outcome.  Potential UPs (i.e., events that are related to the research) 
will be evaluated for expectedness, based on the study.  SAEs related to the investigational 
product will also be evaluated for expectedness, based on that investigational product. 
See Section 17.0 for details of AE annual reporting to the IRB and to the FDA.  
3.2
Clinically Significant Laboratory Abnormalities 
The principal investigator will evaluate all clinical laboratory results for clinically significant 
abnormalities and document the evaluation in a CRF. Clinically significant findings (e.g., 
increase in calcium-citrate ratio to >0.7) will be recorded and reported as AEs regardless of their 
Version Date 20-Dec-2013
Page 8 of 72


association with the use of the investigational product. The principal investigator will follow 
significant abnormalities until they return to baseline or stabilization. 
3.3
SAE & UP Reporting
See Section 17 for details of reporting timeframes for SAEs and UPs to the IRB, Clinical 
Director, and FDA.   
SAEs and UPs will be reported to CROMS product safety via the study specific electronic data 
capture system.  SAEs and UPs should be entered into the EDC within 1 business day of learning 
of the event.  Once submitted, CROMS Product Safety will send a confirmation email to the 
investigator within 1 business day.  The investigator should contact the CROMS product safety if 
this confirmation is not received.  The Product Safety Associate will review the event report, 
gather additional information from the site, as necessary, and consult with the medical monitor or 
the physician designee. 
Together, this Product Safety Team will determine for SAEs whether there is a reasonable 
possibility that the event is related to the investigational product and if so, whether the event was 
expected for the investigational product. The Product Safety Team will also review the intensity 
of the SAE in order to determine follow-up actions.   
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24.2 Pre-Screening Questionnaire and 
Eligibility Checklist 
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Page 10 of 72


If any health problem is Yes, subject is ineligible and skip to end.
Gafni 07-D-0016 
Prescreening  
Subject ID #:  
 Telephone Pre-Screening 
Screening Eligibility Questions
1. [Interviewer] Date of interview:
/
/
dd
mmm
yyyy
2. [Interviewer] What is the subject’s gender?
  
 Male  
  
 Female 
3. What is your date of birth?    
/
/
   OR Age at time of Pre-Screening 
                                   
dd
mmm
yyyy
If subject is permanently ineligible for the study or does not provide 
informed consent, enter Age and leave Date of Birth blank. 
4. Have you been diagnosed with hypoparathyroidism by a physician?
 
 Yes  
 
 No (Ineligible, skip to end)
 
4a.  Were you diagnosed at least one year ago?
 
 
 Yes  
 
 
 No (Ineligible, skip to Q16)
5. Do you have any of the following health problems?
 
 
 
 
 
Diabetes
 Yes       
 No 
Celiac disease
 Yes  
 No 
Crohn's disease
 Yes  
 No 
 
Cushing's 
syndrome
 Yes  
 No 
Active thyroid 
cancer
 Yes  
 No 
Seizure disorder
 Yes  
 No 
Osteoporosis
 Yes  
 No 
Osteosarcoma
 Yes  
 No 
Paget's disease
 Yes  
 No 
 
Metastatic bone 
disease   
 Yes  
 No 
Liver disease   
 Yes  
 No 
Adrenal 
insufficiency   
 Yes  
 No 
Retinoblastoma   
 Yes  
 No 
 
Li-Fraumeni 
Syndrome   
 Yes  
 No 
Other
 Yes  
 No   Specify permanently disqualifying condition:  
6. Are you currently taking any medications?
 
 Yes  
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 No (Skip to Q7)
 6a.  What medications are you taking?
List medications: 
Exclusionary medications: PTH (for more than 2 weeks prior to study entry), thyroid hormone to suppress thyroid stimulating hormone
below the assay's detection limit, bisphosphonates, calcitonin, tamoxifen, selective-estrogen receptor modulators, oral or intravenous  
corticosteroids (>3 weeks in last 6 months), estrogen replacement therapy, or medication for a seizure disorder 
 
6b. [Interviewer] Is the subject taking any exclusionary medications?
 
 
 
 Yes (Ineligible, skip to Q16)
 
 
 
 No 
7.
Are you allergic to any antibiotics?
 
 
 Yes  
 
 
 No (Skip to Q8)
 
7a.  Which antibiotics are you allergic to?
List antibiotics:
 
7b. [Interviewer] Were tetracycline antibiotic allergies noted?
 
 
 Yes (Ineligible, skip to end)
 
 
 No 
8.
Have you received bone radiation treatment?
 
 Yes (Ineligible, skip to end)
 
 No 
9.
[Females only] Have you been post-menopausal for more than 6 months?
[Removed per protocol amendment]
9a. [Interviewer, Females only] Is the subject peri-menopausal as defined by no menses for 6 months to 5 years?
 
 Yes (Ineligible, skip to Q16)
 
 No 
10. [Females only] Are you pregnant or breast-feeding?
 
 Yes (Ineligible, skip to Q16)
 
 No 
11. [Females only] Have you received an injection for birth control in the last 12 months?
 
 Yes (Ineligible, skip to Q16)
 
 No 
12. [Interviewer] Are there any other reasons to exclude this subject?
 
 Yes (Ineligible, provide Comment and skip to Q16)
 
 No (Skip to Q13)
12a. Comment on reason or exclusion:  
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13. [Interviewer]Is the subject eligible for a screening visit?
 
 Yes  
 
 No (Skip to Q16)
14. [Interviewer] Is the subject interested in attending a screening visit?
 
 Yes  
 
 No (Skip to end)
15. [Interviewer] Was an inpatient visit scheduled?
 
 Yes  
 
 No (Skip to Q16)
16.  [Interviewer] Will the subject be contacted later to reassess eligibility for the study?
 
 Yes  
 
 No 
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Gafni 07-D-0016
Subject ID #: 
 Inclusion Criteria
 
 Subjects may only be included if all applicable inclusion questions are answered "Yes".
 
1. Adult female aged 18-45 years or adult male aged 18-50 years
[Removed per
protocol amendment]
 
1a. Pre-menopausal female aged 18-45 years or adult male aged 18-70 years
 Yes
 No
 N/A
 
1b. Postmenopausal woman aged  53 years to 70 years and 5 years since last menses
 Yes
 No
 N/A
 
[2.] Adolescent female with bone age  14 years (x-ray of the hand and wrist) or
adolescent male with bone age  16 years (x-ray of the hand and wrist)
[Removed per
protocol amendment]
 
3. Physician-diagnosed hypoparathyroidism of at least 1-year duration, confirmed
by medical record review
 Yes
 No
 N/A
 
4. Intact PTH < 30 pg/mL
 Yes
 No
 N/A
 
5. Woman without a uterus with a clinical history of menopause for at least 5 years and an
FSH > 30 u/L
 Yes
 No
 N/A
 
 
 Exclusion Criteria
 
 Subjects must be excluded if any responses to questions 1 - 18 are answered "Yes".
 
1. Moderate to severe hepatic disease defined as hepatic transaminases (ALT and
AST) > 2 times the upper limit of normal
 Yes
 No
 N/A
 
2. Severe renal insufficiency defined as a calculated GFR < 25 mL/min/1.73 m2
using the CKD-EPI equation
 Yes
 No
 N/A
 
3. Allergy or intolerance to tetracycline antibiotics
 Yes
 No
 N/A
 
4. Pregnant or lactating
 Yes
 No
 N/A
 
Inclusion/Exclusion
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5. Peri- or post-menopausal as defined by no menses for > 6 months and an
FSH > 20 U/L at the screening and/or baseline visits
[Removed per
protocol amendment]
 
5a. Peri-menopausal defined by no menses for 6 months to 5 years and
an FSH > 20 U/L at the screening and/or baseline visits
 Yes
 No
 N/A
 
6. Chronic diseases that might affect mineral metabolism such as diabetes, celiac
disease, Crohn's disease, Cushing's syndrome, or adrenal insufficiency
 Yes
 No
 N/A
 
7. Concurrent treatment with doses of thyroid hormone intended to suppress
thyroid stimulating hormone below the assay's detection limit or persistent
thyroid cancer
 Yes
 No
 N/A
 
[8.] History of a skeletal disease unrelated to hypoparathyroidism, such as
osteoporosis/low bone density (defined as a DXA Z-score or T-score < -2),
osteosarcoma, Paget's disease, or metastatic bone disease
[Removed per
protocol amendment]
8a. History of a skeletal disease unrelated to hypoparathyroidism, such as osteoporosis or
low bone density (defined as a DXA Z-score < -2 in all subjects or T-score < -2 in
subjects    20 years old), osteosarcoma, Paget’s disease, alkaline phosphatase  > 1.5
times the upper limit of normal, or metastatic bone disease
 Yes
 No
 N/A
 
 
 
 
 
9. History of treatment with bisphosphonates, calcitonin, tamoxifen, selective-
estrogen receptor modulators, or directed skeletal irradiation
 Yes
 No
 N/A
 
10. Use of oral or intravenous corticosteroids for more than
3 weeks within the last 6 months
[Removed per
protocol amendment]
 
10a. Use of oral or intravenous corticosteroids or estrogen replacement therapy for
more than 3 weeks within the last 6 months
 Yes
 No
 N/A
 
11. Use of depot medoxyprogesterone for contraception within the past 12 months
 Yes
 No
 N/A
 
12. Chronic inadequate biochemical control with conventional therapy and/or
calcium infusion dependent
 Yes
 No
 N/A
 
13. Seizure disorder requiring antiepileptic medications
 Yes
 No
 N/A
 
14. Treatment with PTH for more than 2 weeks prior to study entry
[Removed per
protocol amendment]
 
14a. Treatment with PTH for more than 2 weeks continuously at any time prior to study entry
 Yes
 No
 N/A
 
15. Any cognitive impairment that limits the subject’s ability to comply,
independently or through the assistance of a legally authorized representative,
with protocol procedures.
 Yes
 No
 N/A
 
Inclusion/Exclusion
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16. Unwillingness or inability to comply with protocol procedures
[Removed per
protocol amendment]
 
17. History of retinoblastoma or Li-Fraumeni syndrome
 Yes
 No
 N/A
 
18. Open epiphyses as determined by an x-ray of the hand and wrist in subjects <21 years of
age
 Yes
 No
 N/A
 
Eligibility Status
 
Review all responses to the inclusion and exclusion criteria to determine subject eligibility.
 
19. Is the patient eligible for the study
 Yes
 No   
Comments associated with this page:
     
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24.3 Study Schema 
Version Date 20-Dec-2013
Page 17 of 72


Effects of HPTH on Bone in Hypoparathyroidism
Study Months
X
N=10
2-6 (±1)
0
6
12
18
24
30
36
48
54
601
42
~
Newly Recruited Subjects
N = 36
Screening visit
Start conventional
care
Baseline visit
Start HPTH
1st biopsy
performed
X
X
X
Randomized to undergo 2nd biopsy (X)
End HPTH
N=12
N=14
Previously Enrolled and
Currently on Conventional Care
X
N=1
Randomized to undergo 2
biopsy (X)
at 1, 2, or 4 years of HPTH. Follow-up 
every 6 months while on HPTH.
End HPTH
Currently on Conventional Care
N=9
(N=5  enrolled in revised protocol)
X
X
Randomized to undergo 2nd biopsy (X)
at 1, 2, or 4 years of HPTH. Follow-up 
every 6 months while on HPTH.
End HPTH
Enter at baseline visit
Start HPTH
Biopsy before 
conventional care 
considered
1st biopsy
N= 2
N= 2
Previously Enrolled
and Currently on PTH
N = 7
y
End HPTH
Not randomized and will not undergo any 
additional biopsies. Follow-up every 6 
th
hil
HPTH
N= 7
~
Enter follow-up
at next scheduled
6th month visit
months while on HPTH.
1 At this time, subjects will be weaned off HPTH and provided with standard of care medication for a minimum of 3 months (±2weeks) and until the subject has stabilized.  
AE/SAE related to the down titration of HPTH will be reported during this Post-HPTH safety follow-up period.                   
Version Date:  15FEB2011
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24.4 Schedule of Events 
Version Date 20-Dec-2013
Page 19 of 72


Gafni 07-D-0016:  Schedule of Events
Prescreen
Screening
8
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V109
V1110
Target Date (months)
 2-6 
0 
6 
12
18
24
30
36
42
48
54
60
66
Visit Window (weeks)
±4
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
Recruitment and 
Enrollment
Telephone pre-screening
X 
Informed consent 1
X 
Medical History
Medical history
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dietician consultation
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Short Calcium 
Questionnaire
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
SF-36
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fitness Measures
Fatigue Symptom Inventory
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
6-Minute Walk Test
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical Exam
Height/weight
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood Tests
DNA testing (if indicated)
X 
Chem 20 panel
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Complete blood count
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Mineral panel or calcium 
level 2
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Thyroid panel
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
25-OH-vitamin D
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1,25 (OH)2 vitamin D11
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Intact PTH
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone-specific alkaline 
phosphate 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Osteocalcin
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ionized calcium
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Research blood samples for 
storage
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X
24-hr blood sampling 3
X 
Version Date 20-Dec-2013
Page 20 of 72


1  Patients enrolled under the previous version of the protocol who are on conventional therapy will re-enter the study at V0 and be 
re-consented at V0.  Patients enrolled under the previous version of the protocol who are on HPTH will re-enter the study during their 
next scheduled follow-up visit and will be re-consented at that visit.
2 Mineral panels and calcium levels may be repeated as needed to monitor response to PTH therapy.
3  Blood will be drawn every 2 hours (± 15 minutes) for 24 hours to measure calcium, magnesium, phosphorus, and albumin. 
4  At the Screening Visit, single 24-hour urine sample will be collected for calcium, phosphorus, creatinine, magnesium, sodium, citrate, 
pH, and potassium. At all subsequent visits, two 24-hour urine samples will be collected for the same measurements plus the 
measurement of N-Telopeptide. 
5  Radiographs of the hand and wrist to assess bone age will be required for subjects <21 years of age.
6  DXA scan of the spine, femur, radius, and total body.
7  Subjects will be randomized to receive a single follow-up bone biopsy after 1, 2, or 4 years of HPTH therapy.
8 The duration of the screening period will be 2 to 6 months (±1 month) prior to first HPTH dosing.
Gafni 07-D-0016:  Schedule of Events (continued)
Prescreen
Screening8
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V109
V1110
Target Date (months)
2-6 
0 
6 
12
18
24
30
36
42
48
54
60
66
Visit Window (weeks)
±4
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
± 2
Blood Tests
Acute care and mineral 
panels11
X 
FGF2311
X 
Urine Tests
Urine pregnancy test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24-hour urine 4
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Spot Urine12
X 
Imaging
Radiographs to assess bone 
age 5
X 
Renal ultrasound
X 
X 
X 
X 
X 
X 
X 
X 
DXA 6
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT of the kidney without 
contrast
X 
X 
X 
X 
X 
X 
Quantitative CT (L1 and L2 
spine)
X 
X 
X 
X 
X 
X 
Biopsy
Baseline bone biopsy
X 
Follow-up bone biopsy 7
X 
X 
X 
PTH 
Conventional care
X 
X 
X 
PTH therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Version Date 20-Dec-2013
Page 21 of 72


9  At this time point, subjects will have been weaned off HPTH and provided with standard of care medication for a minimum of 3 months 
(± 2weeks) and until the subject has stabilized.  Only AE/SAEs related to the weaning/termination of HPTH will be reported during this 
Post HPTH stabilization phase. 
10 Visit will be completed 6 months after the start of the Post HPTH stabilization phase.
11Blood draws for an acute care panel, mineral panel, 1,25 (OH)2 vitamin D, and FGF23 will be completed at 8AM, 12PM, 4PM, and 8PM 
on the first day of PTH therapy (Day 0). Blood draws for an acute care panel, mineral panel, 1, 25 (OH)2 vitamin D, and FGF23 will also 
be collected at 8AM on the second day of PTH therapy (Day 1). One-hour windows are permitted on either side of each specified 
sampling time.  
A morning blood draw will be completed on subsequent in-patient days during V0 for an acute care panel.
12Spot urine will be collected for cAMP, creatinine, phosphorus, calcium, and pH at 8AM, 12PM, 4PM, and 8PM on the first day of PTH 
therapy (Day 0). Spot urine for cAMP, creatinine, phosphorus, calcium, and pH will also be collected at 8AM on the second day of PTH 
therapy (Day 1). One-hour windows are permitted on either side of each specified sampling time.  
A morning spot urine will be collected on subsequent in-patient days during V0 for cAMP, creatinine, phosphorus, calcium, and pH.  
Version Date 20-Dec-2013
Page 22 of 72


 
 
 
 
 
 
 
 
 
24.5 Calcium Questionnaire 
Version Date 20-Dec-2013
Page 23 of 72


Name:
Date:
Number
Reference
servings
Food or Beverage
serving
per week
For office use only:
"Total"
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Have you taken any of the following in the past month?
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If yes, complete the following:
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1DPHRISURGXFW
TOTAL DAILY CALCIUM INTAKE
mg/day
&DOFLXPPJSHUGRVH
$YHUDJHQXPEHUGRVHVWDNHQSHUZHHN
1DPHRISURGXFW
&DOFLXPPJSHUGRVH
6KRUW&DOFLXP4XHVWLRQQDLUHYHUVLRQ6&4
$YHUDJHQXPEHUGRVHVWDNHQSHUZHHN
1XWULWLRQ'HSDUWPHQW1,+&OLQLFDO&HQWHU
1DWLRQDO,QVWLWXWHVRI+HDOWK%HWKHVGD0'86$
Average calcium (mg/day)
Average calcium (mg/day)
Average calcium (mg/day)
Patient number:
Directions: In the yellow (shaded) boxes below, write in the number of servings of each of the following foods you eat in 
a typical week.
Version Date 20-Dec-2013
Page 24 of 72


 
 
 
 
 
 
 
 
 
24.6 DNA Consent Documents 
Version Date 20-Dec-2013
Page 25 of 72


Informed Consent for CASR
Page 1 of 2
GeneDx 07/07
Informed Consent for DNA Testing
GeneDx, Inc.
207 Perry Parkway
Gaithersburg, MD 20877
Phone: 301-519-2100
Fax: 301-519-2892
E-mail: genedx@genedx.com
www.genedx.com
I, __________________________________________, request DNA-based testing for [circle] MYSELF
and/or MY CHILD or CHILDREN for Calcium Homeostasis Disorder/CASR (name of disease/gene). I
understand that biological samples (blood, cheek cells, or skin) will be removed using standard
techniques which carry very little risk. In addition, if prenatal diagnosis is being performed, fetal cells
obtained by chorionic villus sampling or amniocentesis will be used. I understand that the blood, cheek
cells, skin, or fetal samples will be used for the purpose of attempting to determine if I and/or members
of my family are carriers of the disease gene, or are affected with, or at increased risk to someday be
affected with this genetic disease. The minor children for which I hereby give permission to collect
biological samples for this test are named below:
Childs Name
Date of Birth
Gender (M/F)
_________________________
____________
__________
_________________________
____________
__________
_________________________
____________
__________
I understand that:
1. In some cases the DNA test directly detects an abnormality, called a mutation, in the gene, and the
test is better than 99% accurate.
In other cases, the DNA test is unable to identify an abnormality although the abnormality may
still exist. This event may be due to our current lack of knowledge of the complete gene
structure or an inability of the current technology to identify certain types of changes
(mutations) in the gene.
Ninety percent of families with familial (benign) hypocalciuric hypercalcemia, type 1
(HHC1/FHH) have an identifiable mutation in the CASR gene.  Most cases of autosomal
recessive neonatal severe primary hyperparathyroidism (NSHPT) also harbor mutations
in the CASR gene.  In autosomal dominant hypocalcemia (ADH), one small study found
that 42% of patients with isolated hypoparathyroidism had a CASR mutation.  Test
sensitivity in familial isolated hypoparathyroidism (FIH) has not been established.
Studies in some families with calcium homeostasis disorders have found that mutation
in another gene (or genes), rather than CASR, is likely to underlie the disease; however
those other genes have yet to be identified.
I have been informed of the likelihood of finding a mutation in the gene for which I am being
tested. _____ (Initial)
2. In rare cases, GeneDx may use an indirect method called linkage analysis. If linkage analysis is
being used, naturally occurring rearrangements in the DNA (known as “recombination”) may
produce an uncertainty in predicting carrier status or diagnosis. Rare variations in the DNA of
individuals can also cause uncertainty in predicting carrier status or diagnosis. Thus, linkage
Version Date 20-Dec-2013
Page 26 of 72


Informed Consent for CASR
Page 2 of 2
GeneDx 07/07
analysis is not 100% accurate, and the results will be reported as a probability. In some families, the
markers used for the linkage analysis may not be informative. In these cases, the DNA test will not
be useful for that family or for some family members.
3. An error in the diagnosis of disease status may occur if the true biological relationships of the family
members being tested are not as I have stated. For example, non-paternity means that the stated
father of an individual is not the true biological father. This test may detect non-paternity, and it may
be necessary to report this finding to the individual who requested testing. Any erroneous diagnosis
in a family member can lead to an incorrect diagnosis for other related individuals who are being
tested.
4. I understand that the DNA analysis performed by GeneDx is specific for this disease and in no way
guarantees my health or the health of my living or unborn children. The accuracy of DNA analysis is
entirely dependent on the clinical diagnosis made elsewhere, and GeneDx cannot be responsible
for an erroneous clinical diagnosis made elsewhere.
5. In order to perform accurate prenatal diagnosis on a fetal sample, biological samples are also
required from the affected individual in the family, the mother, and in some cases the father.
6. These tests are relatively new and are being improved and expanded continuously. The tests are
not considered research, but are considered to be the best and newest laboratory service that can
be offered. This testing is complex and utilizes specialized materials so that there is always some
very small possibility that the test will not work properly or that an error will occur. There is a low
error rate (perhaps 1 in 1000 samples) even in the best laboratories. My signature below
acknowledges my voluntary participation in this test, but in no way releases the laboratory and staff
of GeneDx from their professional and ethical responsibility to me.
7. I understand that my sample is not being banked. GeneDx does not return DNA samples to
individuals or physicians. However, in some cases it may be possible for GeneDx to reanalyze the
remaining DNA upon request. The request for additional testing must be ordered and there will be
an additional fee.
8. Because of the complexity of DNA based testing and the important implications of the test results,
results will only be reported to me through a physician, genetic counselor, or certified genetics
professional. The result reports are confidential and will only be released to other medical
professionals or other parties with my express written consent. All laboratory data is confidential
and will not be released from GeneDx. Participation in DNA testing is completely voluntary.
9. I will receive a copy of this consent form.
Signature: _________________________________________ Date:   ___________________
Witnessed by:  _____________________________________
Physicians/Counselors Statement:  I have explained DNA testing to this individual. I have
addressed the limitation outlined above, and I have answered this persons questions.
Signature: _________________________________________ Date:  ____________________
Version Date 20-Dec-2013
Page 27 of 72


 
 
 
Informed Consent for AIRE                                       Page 1 of 2                                                                          GeneDx 1/09 
Informed Consent for DNA Testing 
GeneDx 
207 Perry Parkway 
Gaithersburg, MD 20877 
Phone: 301-519-2100 
Fax: 301-519-2892 
E-mail: genedx@genedx.com 
www.genedx.com  
 
 
I, __________________________________________, request DNA-based testing for [circle] MYSELF 
and/or MY CHILD or CHILDREN for Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal 
Dystrophy / AIRE gene (name of disease/gene). I understand that biological samples (blood, cheek 
cells, or skin) will be removed using standard techniques which carry very little risk. In addition, if 
prenatal diagnosis is being performed, fetal cells obtained by chorionic villus sampling or amniocentesis 
will be used. I understand that the blood, cheek cells, skin, or fetal samples will be used for the purpose 
of attempting to determine if I and/or members of my family are carriers of the disease gene, or are 
affected with, or at increased risk to someday be affected with this genetic disease. The minor children 
for which I hereby give permission to collect biological samples for this test are named below:  
 
Childs Name  
 
 
 
Date of Birth  
 
Gender (M/F) 
 
_________________________ 
 
____________ 
 
__________ 
 
_________________________ 
 
____________ 
 
__________ 
 
_________________________ 
 
____________ 
 
__________ 
 
I understand that: 
 
1. In some cases the DNA test directly detects an abnormality, called a mutation, in the gene, and the 
test is better than 99% accurate. 
 
In other cases, the DNA test is unable to identify an abnormality although the abnormality may still 
exist. This event may be due to our current lack of knowledge of the complete gene structure or an 
inability of the current technology to identify certain types of changes (mutations) in the gene. 
 
Tier 1 of the AIRE test (sequencing of exons 2, 3, 6, 8, and 10) is expected to detect at least 
one mutation in 90% of patients in most ethnic groups. Tier 2 testing (sequencing of the 
remainder of the gene plus exon-level array CGH if indicated) is available for patients who 
are negative or have only one mutation with Tier 1. Altogether the methods use by GeneDx 
are expected to detect at least 98% of mutations. 
 
I have been informed of the likelihood of finding a mutation in the gene for which I am being tested. 
______  (Initial) 
 
2. In rare cases, GeneDx may use an indirect method called linkage analysis. If linkage analysis is 
being used, naturally occurring rearrangements in the DNA (known as “recombination”) may 
produce an uncertainty in predicting carrier status or diagnosis. Rare variations in the DNA of 
individuals can also cause uncertainty in predicting carrier status or diagnosis. Thus, linkage 
analysis is not 100% accurate, and the results will be reported as a probability. In some families, the 
markers used for the linkage analysis may not be informative. In these cases, the DNA test will not 
be useful for that family or for some family members. 
 
Version Date 20-Dec-2013
Page 28 of 72


Informed Consent for AIRE                                          Page 2 of 2                                                                       GeneDx 1/09 
3. An error in the diagnosis of disease status may occur if the true biological relationships of the family 
members being tested are not as I have stated. For example, non-paternity means that the stated 
father of an individual is not the true biological father. This test may detect non-paternity, and it may 
be necessary to report this finding to the individual who requested testing. Any erroneous diagnosis 
in a family member can lead to an incorrect diagnosis for other related individuals who are being 
tested. 
 
4. I understand that the DNA analysis performed by GeneDx is specific for this disease and in no way 
guarantees my health or the health of my living or unborn children. The accuracy of DNA analysis is 
entirely dependent on the clinical diagnosis made elsewhere, and GeneDx cannot be responsible 
for an erroneous clinical diagnosis made elsewhere. 
 
5. In order to perform accurate prenatal diagnosis on a fetal sample, biological samples are also 
required from the affected individual in the family, the mother, and in some cases the father.   
 
6. These tests are relatively new and are being improved and expanded continuously. The tests are 
not considered research, but are considered to be the best and newest laboratory service that can 
be offered. This testing is complex and utilizes specialized materials so that there is always some 
very small possibility that the test will not work properly or that an error will occur. There is a low 
error rate (perhaps 1 in 1000 samples) even in the best laboratories. My signature below 
acknowledges my voluntary participation in this test, but in no way releases the laboratory and staff 
of GeneDx from their professional and ethical responsibility to me. 
 
7. I understand that my sample is not being banked. GeneDx does not return DNA samples to 
individuals or physicians. However, in some cases it may be possible for GeneDx to reanalyze the 
remaining DNA upon request. The request for additional testing must be ordered and there will be 
an additional fee. 
 
8. Because of the complexity of DNA based testing and the important implications of the test results, 
results will only be reported to me through a physician, genetic counselor, or certified genetics 
professional. The result reports are confidential and will only be released to other medical 
professionals or other parties with my express written consent. All laboratory data is confidential 
and will not be released from GeneDx. Participation in DNA testing is completely voluntary. 
 
9. I will receive a copy of this consent form. 
 
Signature: _________________________________________ Date:   ___________________ 
 
Witnessed by:  _____________________________________ 
 
Physicians/Counselors Statement:  I have explained DNA testing to this individual. I have 
addressed the limitation outlined above, and I have answered this persons questions. 
 
Signature: _________________________________________ Date:  ____________________ 
Version Date 20-Dec-2013
Page 29 of 72


 
 
 
 
 
 
 
 
 
24.7 SF-36 Survey 
Version Date 20-Dec-2013
Page 30 of 72


Version Date 20-Dec-2013
Page 31 of 72


Version Date 20-Dec-2013
Page 32 of 72


Version Date 20-Dec-2013
Page 33 of 72


Version Date 20-Dec-2013
Page 34 of 72


Version Date 20-Dec-2013
Page 35 of 72


 
 
 
 
 
 
 
 
 
24.8 Fatigue Symptom Inventory 
Version Date 20-Dec-2013
Page 36 of 72


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  
      


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    %! #   !     ! "  "# "   
     &!  ' !   (# )# *()+ %! ,-. ".
  &     ! #          &! $ "# 
" %! () & ""# "   "       "  !"!#
 " ) !  #
 ! () & "      " ! "  "  "
 
  &""   " 
 &!  #     . 
" &    !  " #
 &!  /  0 1 "# &
   &!        1  "# &  
 &!    "     &""       
   2  !     ""
 ! () &  ! "!   "
 ""         %! " "  !    #!"
"# !   
   
 3"
 4 "#  "
	

	
    !    ".
 # !   
5,
 6 )  #
 ! #     
  $ "#  " !  
        ! 
 
 ! !      2
  "      
 %!     .
"  # *
  " " "+ 
 ""    !  ! 7 .
  (" *7(+ 5-6 !   "  !
   "  ! 8  9 
:!  %  1 4 "# 
; 4  5<6  !  ""
  )# 5=6 %!   #.
! "  !  .
  & &      5>6
:"#
 ! 7 " !  
 
"   !  "?  &
 ! ""&
%!  7(   . ".  
    !  @    
   "   ! !"
 2
#
       5A6 %!
7( "  ! . $ 
  &!  !    "  
&! !# "    
  #
 &!   :""#  ! 7( 

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0= C!"  ! ! "  
 !
&    ! 7(  ""  
!    "#   

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 
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	   
	! 	   "	
!
B<A
Version Date 20-Dec-2013
Page 37 of 72


 !  "#    ""#  .
  E   !    
    " !    !  .
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*1%.+ 5B6 %!    " 
 " # * F 0=+  &"" 

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	&
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= 
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" ! "  " &!  " " "
!  !  ! "    ! !  
 "       G
 
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 
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 "        
 
      !  ".
"      $ "#  "
%! (!&9 1   (" *(1(+ 506 
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 
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 :""#     &
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 "
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" 
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    !
   ! "  
    #
  
   
$ "#  " %!   # #
*()+ 2 !  $   #   .
  #
    
  ! .
    &!     $ "# 
" 5>6 %! #!   ! ()
& ""#    "  &
     
 &
&! ! "    
 & &!  !#   %! 
  "" !    & &   ==
# ) !  #
 ! . 
 " &    !  " .
#
 &!  /  0  "" !
  %! " () &    !
! &   D ""# 
   !"!# "  
!   1 "# &
    &!  
9     1  "#
&     &
 &!    &""   &!
   #   ""
 !
() & "!   "  ""  
         !"!#
 " 	&
  " !   #
 !
() !     !  
%!    !     ! #.
!   ! () &!   &!
"   &""  " 
 
== #    "  &""    
== #  
   &! ! # 
  &""   &!  


 #
%  ""  ! "
  !  
,B #    "
 !  & #!.
   ""  &!! & " .
 &! "  !  
   "
  8"! 7 &     .
 "     *)&
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 .

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   !   " ! & 
    >K  "  -<
    !  #
		
8!  @ &  ""#   #  "
2   !   
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  &  
". $   " &!" &
 !  7 &! &! 
" ! $   ! & 
  " &! &!!     )
  ! ()
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( *7(.+ 5,6
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 ,6
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B<B
Version Date 20-Dec-2013
Page 38 of 72


   *& +   !  & 
&""    " * + &!!   !
  &!!    &! $ "# 
" %! #  $   H
  ! 
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 &
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* F   ""    , F  .
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 " &!
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  &    ,,   "
* F    , F  .
+ %! " &      

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!    ! # * F   ! #
 , F !  #+   &  5>6
%! 7(.   ""  "   
"  &  "& # 5,6 :.
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Version Date 20-Dec-2013
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24.9 Six-Minute Walk Test 
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The Six-Minute Walk Test
Paul L Enright MD
Introduction
Standards and Indications
6-Minute Walk Test Versus Shuttle Walk Test
Safety
Variables Measured
Conducting the Test
Ensuring Quality
Factors That Influence 6-Minute Walk Distance
Interpreting the Results
Improving the 6-Minute Walk Distance
Summary
The American Thoracic Society has issued guidelines for the 6-minute walk test (6MWT). The 6MWT
is safer, easier to administer, better tolerated, and better reflects activities of daily living than other walk
tests (such as the shuttle walk test). The primary measurement is 6-min walk distance (6MWD), but
during the 6MWT data can also be collected about the patient’s blood oxygen saturation and perception
of dyspnea during exertion. When conducting the 6MWT do not walk with the patient and do not assist
the patient in carrying or pulling his or her supplemental oxygen. The patient should walk alone, not
with other patients. Do not use a treadmill on which the patient adjusts the speed and/or the slope. Do
not use an oval or circular track. Use standardized phrases while speaking to the patient, because your
encouragement and enthusiasm can make a difference of up to 30% in the 6MWD. Count the laps with
a lap counter. If the 6MWD is low, thoroughly search for the cause(s) of the impairment. Better 6MWD
reference equations will be published in the future, so be sure you are using the best available reference
equations. Key words: step test, exercise test, pulmonary rehabilitation. [Respir Care 2003;48(8):783–785.
© 2003 Daedalus Enterprises]
Introduction
Walking tests have been around since the 1960s, when the
12-min walk was popularized by aerobics fitness enthusiast,
Kenneth H Cooper, as a quick and easy fitness test. There’s
a full range of tests that you could perform to assess a pa-
tient’s functional capacity. The easiest is just a questionnaire
or self-report of how much work the patient can do. You
might ask, “How many flights of stairs can you climb or how
many blocks can you walk?” But patients differ in their abil-
ity to recall that kind of information and may overestimate or
underestimate their true functional capacity, so objective mea-
surements are usually better than self-reports. Another easy
test of fitness is the number of stairs the patient can climb.
Many surgeons have said that if the patient can walk up 2–3
flights of stairs, then he or she can survive surgery. The ease
of performing a 6-minute walk test (6MWT) falls between
stair climbing and testing for exercise-induced asthma.
Paul L Enright MD is affiliated with the Respiratory Science Center,
College of Medicine, University of Arizona, Tucson, Arizona.
Dr Enright presented a version of this report at the 18th Annual New
Horizons Symposium, Pulmonary Function Testing in 2002: Updates and
Answers, October 6, 2002, at the American Association for Respiratory
Care’s 48th International Respiratory Congress in Tampa, Florida.
Paul L Enright MD, University of Arizona, AHSC 2342, PO Box 245030, 1501
N Campbell Avenue, Tucson AZ 85724-3030. E-mail: lungguy@aol.com.
RESPIRATORY CARE • AUGUST 2003 VOL 48 NO 8
783
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Standards and Indications
Recently the American Thoracic Society Pulmonary
Function Standards Committee developed guidelines for
the 6MWT in clinical settings.1 Carl Mottram, a respira-
tory therapist working at the Mayo Clinic in Rochester,
Minnesota, helped to review the document. The 6MWT
was chosen because it is easier to administer, better toler-
ated, and better reflects activities of daily living than other
walk tests.2
Table 1 lists the indications for the 6MWT, the most
important of which is to measure outcomes before and
after treatment in people with moderate to severe heart
and lung disease. The 6MWT can also be used to mea-
sure functional status and for epidemiologic purposes.
A short 6-minute walk distance (6MWD) fairly accu-
rately predicts morbidity and mortality from heart or
lung disease.
6-Minute Walk Test Versus Shuttle Walk Test
How does the 6MWT compare to the shuttle walk test,
which is frequently used in Great Britain? With the 6MWT
the instructions to the patient are to “walk as far as you can
during 6-minutes,” whereas the shuttle walk test pressures
the patient to meet multiple deadlines, according to beeps
from an audio cassette tape.3 The 6MWT is self-paced,
and a patient is probably less likely to push himself be-
yond his endurance or through angina or other pain than
during the shuttle walk test. The shuttle walk test is better
correlated with peak oxygen uptake, as measured by a full
cardiopulmonary exercise test, but not as many people are
using the shuttle walk test.
Safety
What about safety? Absolute contraindications for the
6MWT include a history of unstable angina or a heart
attack during the previous month. Relative contraindica-
tions include resting tachycardia (heart rate  120 beats/
min) or uncontrolled hypertension. Two large studies of
thousands of elderly people who performed the 6MWT
reported no untoward events.4,5 A physician need not be
present during the test, but it is recommended that tech-
nicians administering the test be certified in cardiopulmo-
nary resuscitation and that medications be available to
treat angina, bronchospasm, and severe shortness of breath.
Electrocardiographic and oxygen saturation monitoring are
not necessary, and the patient should not be tethered with
cables during the test.
Variables Measured
What variables can be measured in the 6MWT? The
primary measurement is the total distance walked. Sec-
ondary measures can include fatigue and dyspnea, mea-
sured with a modified Borg or visual analog scale. Arterial
oxygen saturation can also be measured via pulse oxime-
try, as long as the oximeter is portable and not heavy.
However, I have used 3 different pulse oximeters in large
epidemiologic studies during the past 10 years, and I found
an unacceptably high failure rate, due to motion artifact.
For the last 2 studies I chose fourth-generation pulse oxime-
ters specifically designed to compensate for motion arti-
fact. They are reliable for determining the oxygen satura-
tion before and after the 6MWT test, but, in my opinion,
you should be very cautious in interpreting oxygen satu-
ration readings obtained during exercise.
Conducting the Test
When you schedule a walk test, ask the patient to wear
comfortable footwear. During the test do not walk with the
patient, because even if you walk behind them, it will alter
their pace. If the patient is using supplemental oxygen
during the walk, don’t help push the oxygen tank or the
6MWD will not be the same as if the patient was pushing
the tank, as he or she would do at home. In one study the
investigators walked 6 people at the same time, which
created competition among the study participants, result-
ing in a 30% larger mean 6MWD than tests in which the
patients walked alone.4
Ensuring Quality
What should you do to obtain good quality results?
Follow the recently published American Thoracic Society
guidelines.1 Do not use a treadmill or bike on which the
Table 1.
Indications for the 6-Minute Walk Test
Before-and-After Treatment Comparisons
Lung transplantation or lung resection
Lung volume reduction surgery
Pulmonary rehabilitation
Drug therapy for chronic obstructive pulmonary disease
Pulmonary hypertension
Heart failure
To Measure Functional Status
Chronic obstructive pulmonary disease
Cystic fibrosis
Heart failure
Peripheral vascular disease
In elderly patients
To Predict Hospitalization and Death
From heart failure, chronic obstructive pulmonary disease, or
pulmonary hypertension
THE SIX-MINUTE WALK TEST
784
RESPIRATORY CARE • AUGUST 2003 VOL 48 NO 8
Version Date 20-Dec-2013
Page 47 of 72


patient adjusts the speed and/or the slope. Do not walk
with the patient. Do not use an oval or circular track. You
must use standardized phrases for speaking to the patient,
because the amount of encouragement and enthusiasm
given can make a difference of up to 30% in the 6MWD.
Count the laps with a lap counter.
Factors That Influence 6-Minute Walk Distance
Table 2 lists factors that influence 6MWD.5 Not sur-
prisingly, short people and women have a shorter stride
length and therefore have shorter 6MWDs. Older and
heavier subjects usually have reduced muscle mass and,
therefore, shorter 6MWDs, as do those who are less mo-
tivated or have impaired cognition. Arthritis and other
musculoskeletal diseases also decrease the 6MWD.
Interpreting the Results
Once you have measured 6MWD for a given patient,
how do you interpret the result? Ideally, you would cal-
culate the predicted distance using equations from a pub-
lished study of healthy people of the same age group,
much like for spirometry tests. Healthy subjects’ 6MWDs
range from 400 to 700 m. However, the few published
studies have all used different methods, and the predicted
distances differ by up to 30% between the studies.5–7 Look
for better 6MWD reference equations to be published in
the future. A low 6MWD is nonspecific and nondiagnostic
(just like a low maximum voluntary ventilation). If the
6MWD is low, thoroughly search for the cause(s) of the
impairment. The following tests may then be helpful: pul-
monary function, cardiac function, ankle-arm index, mus-
cle strength, nutritional status, orthopedic function, and
cognitive function.
Improving the 6-Minute Walk Distance
How much will an intervention improve the 6MWD?
One good study showed that an improvement of more than
70 m walked was clinically important to the patients.8
Meanimprovementsof70–170m(12–40%longer6MWD)
have been published for various interventions. Supplemen-
tal oxygen for chronic obstructive pulmonary disease and
interstitial lung disease was shown to improve 6MWD,
despite the extra weight of the ambulatory oxygen source.
Lung volume reduction surgery has also been shown to
improve 6MWD. In patients with chronic obstructive pul-
monary disease, inhaled bronchodilators and rehabilitation
programs can increase 6MWD.
Summary
The 6MWT is a useful measure of functional capacity,
targeted at people with at least moderately severe impair-
ment. It has been widely used for measuring the response
to therapeutic interventions for pulmonary and cardiac dis-
ease. The new American Thoracic Society guidelines pro-
vide a standardized approach for performing the test.
REFERENCES
1. ATS statement: guidelines for the six-minute walk test. ATS Com-
mittee on Proficiency Standards for Clinical Pulmonary Function
Laboratories. Am J Respir Crit Care Med 2002;166(1):111–117.
2. Solway S, Brooks D, Lacasse Y, Thomas S. A qualitative systematic
overview of the measurement properties of functional walk tests
used in the cardiorespiratory domain. Chest 2001;119(1):256–270.
3. Revill SM, Morgan MDL, Singh SJ, Williams J, Hardman AE. The
endurance shuttle walk: a new field test for the assessment of en-
durance capacity in chronic obstructive pulmonary disease. Thorax
1999;54(3):213–222.
4. Roomi J, Johnson MM, Waters K, Yohannes A, Helm A, Connolly MJ.
Respiratory rehabilitation, exercise capacity and quality of life in chronic
airways disease in old age. Age Ageing 1996;25(1):12–16.
5. Enright PL, McBurnie MA, Bittner V, Tracy RP, McNamara R,
Arnold A, et al. The 6 minute walk test: a quick measure of func-
tional status in elderly adults. Chest 2003;123(2):387–398.
6. Enright PL, Sherrill DL. Reference equations for the six-minute walk
in healthy adults. Am J Respir Crit Care Med 1998;158(5 Pt 1):
1384–1387.
7. Gibbons WJ, Fruchter N, Sloan S, Levy RD. Reference values for a
multiple repetition 6-minute walk test in healthy adults older than 20
years. J Cardiopulm Rehabil 2001;21(2):87–93.
8. Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpret-
ing small differences in functional status: The Six Minute Walk test
in chronic lung disease patients. Am J Respir Crit Care Med 1997;
155(4):1278–1282.
Table 2.
Factors That Affect 6-Minute Walk Distance
Factors Associated with Shorter 6-Minute Walk Distance
Shorter height (shorter legs)
Old age
Higher body weight
Female gender
Impaired cognition
Shorter walking corridor (more turns)
Chronic obstructive pulmonary disease, asthma, cystic fibrosis,
interstitial lung disease
Angina, myocardial infarction, congestive heart failure, stroke,
transient ischemic attack, peripheral vascular disease, ankle-arm
index
Arthritis; ankle, knee, or hip injuries; muscle wasting
Factors Associated with Longer 6-Minute Walk Distance
Taller height (longer legs)
Male gender
High motivation
Patient has previously performed the test
Medication for a disabling disease taken just before the test
Oxygen supplementation
THE SIX-MINUTE WALK TEST
RESPIRATORY CARE • AUGUST 2003 VOL 48 NO 8
785
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24.10 Dosing Algorithm 
Version Date 20-Dec-2013
Page 49 of 72


Version 3.0 
 
24FEB2011 
 
PTH Dosing Algorithm 
Prior to any change in PTH dose, subject compliance, symptoms, and general state of 
health must be assessed by a member of the protocol team.   
If the current dose of PTH is < 5 mcg/dose, PTH will be adjusted at the investigator’s 
discretion. 
Serum Calcium Level
Dose Titration
 < 6.0 mg/dL 
 < 1.5 mmol/L 
x
Calcium 1000-1800 mg PO as a single dose. 
x
Refer to the Emergency Department for calcium infusion  
x
Increase PTH dose by 20-50% 
x
Check serum calcium within 2 – 3 days 
6.1  to 6.9 mg/dL 
1.52  to 1.73 mmol/L 
x
Increase PTH dose 10 to 20%  
x
Calcium 1000mg to 1800 mg PO as a single dose 
x
Check serum calcium within 2 – 3 days 
7.0 – 7.5 mg/dL 
1.75 – 1.88 mmol/L 
x
Increase PTH dose 5 to 20% and/or Calcium 500 – 1200 mg PO as a single 
dose  
x
Check serum calcium at least once within a week of dosing change 
7.6 – 9.0 mg/dL 
1.9 – 2.25 mmom/L 
x
No change or 5% increase/decrease in PTH dose or increase/decrease in 
calcium supplements 
x
Check serum calcium at least once a month 
x
If change in dose was made, recheck calcium within one week 
9.1 – 10.9 mg/dL 
2.28 – 2.73 mmol/L 
x
Decrease PTH dose 5 to 20% and/or decrease oral calcium supplements 
x
Check serum calcium once a week until calcium level is back to target range. 
11.0  - 11.9 mg/dL 
2.75 – 2.98 mmol/L 
x
Temporarily suspend PTH dosing and calcium supplements  
x
Check serum calcium within 2 – 3 days 
x
Resume PTH dosing, decreased 20-40 % when serum calcium < 11.0 mg/dL, 
2.75 mmol/L 
> 12.0 mg/dL 
> 3 mmol/L 
x
Temporarily suspend dosing and calcium supplements 
x
Refer to the Emergency Department for IV fluids 
x
Check serum calcium within 2 – 3 days  
x
Resume dosing, decreased 20-40 % when serum calcium < 11.0 mg/dL, 2.75 
mmol/L 
Version Date 20-Dec-2013
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24.11 Discharge Instructions 
Version Date 20-Dec-2013
Page 51 of 72


v3.0                     
 
13SEP11 
Discharge Instructions for Patients on Protocol 07-D-0016
 
Name:  
 
 
 
   
 
Date of Discharge:  
 
 
Diet: 
 
Please make sure to get at least 1000-2000 mg of calcium every day.  If you are unable to 
get enough calcium through your diet, you may take supplements as directed below.  
Please do not drink a lot of cola as it contains lots of phosphorus which is not good in 
hypoparathyroidism.  Limiting your salt intake may help to decrease the amount of 
calcium in your urine and is recommended in general for good health. 
 
Medication doses and instructions:
 
HPTH (100 mcg/mL):  Inject _____ mL twice a day (this is ___ on an insulin syringe) 
Calcium supplements: ____________________________________________________ 
Magnesium supplements:__________________________________________________ 
Other:   
 
Outside Laboratory Tests:
 
1.  Please use the slip that we have given you to obtain laboratory tests near your home. 
2.  You must do blood tests at least once a month and urine tests every three months.  
Please make sure that your lab has faxed the results to 301-435-7598. 
 
Your next blood test is due the week of: ______________________  
Your next 24-hour urine collection is due the week of: _____________________ 
Illnesses or other issues:
 
Please contact Dr. Rachel Gafni (301-594-9924) or Nurse Lori Guthrie (301-594-0844) 
as soon as possible if you are sick, injured, or start taking any new medications.  Please 
have someone contact us immediately if you need to go to the emergency room or are 
hospitalized.    For evening and weekend emergencies, please call the NIH page operator 
at 301-496-1211 and ask to page Dr. Gafni. 
 
I understand that if I am unable to follow the instructions above, I may be taken off 
of HPTH and withdrawn from this protocol. 
________________________________ 
________________________________ 
 
Subject and date 
 
 
 
Investigator and date 
________________________________ 
Witness and date 
Version Date 20-Dec-2013
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24.12 Bone Labeling Instructions  
Version Date 20-Dec-2013
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V2.0 
                                                                                                  30AUG12 
Bone “Labeling” Instruction Sheet for Biopsy - Tetracycline 
 
Certain antibiotics are taken-up by bone.   When a specimen of bone that has 
incorporated these antibiotics is subjected to light of a particular wave length, it is 
fluorescent.  When these antibiotics are given in a specific sequence with a length of time 
between doses, the bone is “labeled” in such a way that an enormous amount of 
information can be gained about the bone’s biology.  During this study there will be two 
biopsies.  Different antibiotics and combinations of antibiotics will be used for different 
biopsies 
 
For this biopsy, we will use the antibiotic tetracycline according to the following 
schedule:  3 days of tetracycline (250 mg 4 times per day), 12 days off drug, 3 days of 
tetracycline (250 mg 4 times per day), four days off drug and biopsy on the fifth day.   
 
Your schedule is indicated below.    You should not take these antibiotics if you have an 
allergy to tetracycline-type antibiotics, are under 6 years of age or pregnant.  In addition, 
you should avoid extensive direct sun light while you are actively taking these antibiotics.  
 
Patient: ______________________________ 
 
       Day # 
      Date 
Drug 
1  
 
tetracycline 250 mg 4 times/day 
2   
 
tetracycline 250 mg 4 times/day 
3 
 
tetracycline 250 mg 4 times/day 
4 
 
 
5 
 
 
6 
 
 
7 
 
 
8 
 
 
9 
 
 
10 
 
 
11 
 
 
12 
 
 
13  
 
 
14  
 
 
15 
 
 
16 
 
tetracycline 250 mg 4 times/day 
17 
 
tetracycline 250 mg 4 times/day 
18 
 
tetracycline 250 mg 4 times/day 
19  
 
 
20 
 
 
21 
 
 
22 
 
 
23  Biopsy 
 
Biopsy 
 
Version Date 20-Dec-2013
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V2.0 
                                                                                                  30AUG12 
Bone “Labeling” Instruction Sheet Biopsy - Demeclocycline 
 
Certain antibiotics are taken-up by bone.   When a specimen of bone that has 
incorporated these antibiotics is subjected to light of a particular wave length, it is 
fluorescent.  When these antibiotics are given in a specific sequence with a length of time 
between doses, the bone is “labeled” in such a way that an enormous amount of 
information can be gained about the bone’s biology.  During this study there will be two 
biopsies.  Different antibiotics and combinations of antibiotics will be used for different 
biopsies 
 
For this biopsy, we will use the antibiotic demeclocycline according to the following 
schedule:  3 days of demeclocycline (150 mg 4 times per day), 12 days off drug, 3 days 
of demeclocycline (150 mg 4 times per day), four days off drug and biopsy on the fifth 
day.   
 
Your schedule is indicated below.    You should not take these antibiotics if you have an 
allergy to tetracycline-type antibiotics, are under 6 years of age or pregnant.  In addition, 
you should avoid extensive direct sun light while you are actively taking these antibiotics.  
 
Patient: ______________________________ 
       Day # 
      Date 
Drug 
1  
 
demeclocycline 150 mg 4 times/day 
2   
 
demeclocycline 150 mg 4 times/day 
3 
 
demeclocycline 150 mg 4 times/day 
4 
 
 
5 
 
 
6 
 
 
7 
 
 
8 
 
 
9 
 
 
10 
 
 
11 
 
 
12 
 
 
13  
 
 
14  
 
 
15 
 
 
16 
 
demeclocycline 150 mg 4 times/day 
17 
 
demeclocycline 150 mg 4 times/day 
18 
 
demeclocycline 150 mg 4 times/day 
19  
 
 
20 
 
 
21 
 
 
22 
 
 
23  Biopsy 
 
Biopsy 
 
Version Date 20-Dec-2013
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24.13 Forteo Package Insert 
Version Date 20-Dec-2013
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1
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use 
FORTEO safely and effectively. See full prescribing information for 
FORTEO.
FORTEO (teriparatide [rDNA origin] injection) for subcutaneous use
Initial U.S. Approval: 2002
WARNING: POTENTIAL RISK OF OSTEOSARCOMA
See full prescribing information for complete boxed warning.
•
In rats, teriparatide caused an increase in the incidence of 
osteosarcoma, a malignant bone tumor. (5.1, 13.1)
•
Because of the uncertain relevance of the rat osteosarcoma finding to 
humans, prescribe FORTEO only for patients for whom potential 
benefits outweigh potential risk. (5.1)
•
FORTEO should not be prescribed for patients at increased baseline 
risk for osteosarcoma (e.g., those with Paget’s disease of bone or 
unexplained elevations of alkaline phosphatase, pediatric and young 
adult patients with open epiphyses, or prior external beam or implant 
radiation therapy involving the skeleton). (5.1)
--------------------------- RECENT MAJOR CHANGES --------------------------
None.
----------------------------INDICATIONS AND USAGE ---------------------------
FORTEO is recombinant human parathyroid hormone analog (1-34), 
[rhPTH(1-34)] indicated for:
•
Treatment of postmenopausal women with osteoporosis at high risk for 
fracture (1.1)
•
Increase of bone mass in men with primary or hypogonadal osteoporosis at 
high risk for fracture (1.2)
•
Treatment of men and women with osteoporosis associated with sustained 
systemic glucocorticoid therapy at high risk for fracture (1.3)
----------------------- DOSAGE AND ADMINISTRATION ----------------------
•
Recommended dose is 20 mcg subcutaneously once a day (2.1, 2.2, 2.3)
•
Administer as a subcutaneous injection into the thigh or abdominal wall 
(2.4)
•
Administer initially under circumstances in which the patient can sit or lie 
down if symptoms of orthostatic hypotension occur (2.4)
•
Use of the drug for more than 2 years during a patient’s lifetime is not 
recommended (2.5)
----------------------DOSAGE FORMS AND STRENGTHS ---------------------
Multi-dose prefilled delivery device (pen) containing 28 daily doses of 20 
mcg (3)
-------------------------------CONTRAINDICATIONS------------------------------
•
Patients with hypersensitivity to teriparatide or to any of its excipients (4)
------------------------ WARNINGS AND PRECAUTIONS -----------------------
•
Patients with Paget’s disease of bone, pediatric and young adult patients 
with open epiphyses, and patients with prior external beam or implant 
radiation involving the skeleton: Should not be treated with FORTEO (5.1,
8.4)
•
Treatment duration: Use of FORTEO for more than 2 years during a 
patient’s lifetime is not recommended. (5.2)
•
Patients with bone metastases, history of skeletal malignancies, metabolic 
bone diseases other than osteoporosis, or hypercalcemic disorders: Should
not be treated with FORTEO (5.3, 5.4, 5.5)
•
Laboratory alterations: FORTEO may increase serum calcium, urinary 
calcium, and serum uric acid (5.5, 5.6)
•
Urolithiasis: Use with caution in patients with active or recent urolithiasis 
because of risk of exacerbation (5.6)
•
Orthostatic hypotension: Transient orthostatic hypotension may occur with 
initial doses of FORTEO (5.7)
-------------------------------ADVERSE REACTIONS------------------------------
Most common adverse reactions (>10%) include: arthralgia, pain, and nausea 
(6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and 
Company at 1-800-545-5979 or FDA at 1-800-FDA-1088 or 
www.fda.gov/medwatch
------------------------------- DRUG INTERACTIONS ------------------------------
Digoxin: Use FORTEO with caution in patients receiving digoxin. Transient 
hypercalcemia may predispose patients to digitalis toxicity (5.8, 7.1, 12.3)
------------------------USE IN SPECIFIC POPULATIONS-----------------------
•
Pregnancy: Based on animal studies, may cause fetal harm (8.1)
•
Nursing Mothers: Discontinue nursing or FORTEO, taking into account 
the importance of treatment to the mother (8.3)
•
Pediatric Use: FORTEO should not be used in pediatric and young adult 
patients with open epiphyses due to increased baseline risk of 
osteosarcoma (5.1, 8.4)
See 17 for PATIENT COUNSELING INFORMATION and Medication 
Guide
Revised: 03/2012
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: POTENTIAL RISK OF OSTEOSARCOMA
1
INDICATIONS AND USAGE
1.1
Treatment of Postmenopausal Women with Osteoporosis at 
High Risk for Fracture
1.2
Increase of Bone Mass in Men with Primary or Hypogonadal 
Osteoporosis at High Risk for Fracture
1.3
Treatment of Men and Women with Glucocorticoid-Induced 
Osteoporosis at High Risk for Fracture
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of Postmenopausal Women with Osteoporosis at 
High Risk for Fracture
2.2
Increase of Bone Mass in Men with Primary or Hypogonadal 
Osteoporosis at High Risk for Fracture
2.3
Treatment of Men and Women with Glucocorticoid-Induced 
Osteoporosis at High Risk for Fracture
2.4
Administration
2.5
Treatment Duration
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1
Osteosarcoma
5.2
Treatment Duration
5.3
Bone Metastases and Skeletal Malignancies
5.4
Metabolic Bone Diseases
5.5
Hypercalcemia and Hypercalcemic Disorders
5.6
Urolithiasis or Pre-existing Hypercalciuria
5.7
Orthostatic Hypotension
5.8
Drug Interactions
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
6.2
Postmarketing Experience
7
DRUG INTERACTIONS
7.1
Digoxin
7.2
Hydrochlorothiazide
7.3
Furosemide
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
8.3
Nursing Mothers
8.4
Pediatric Use
8.5
Geriatric Use
8.6
Hepatic Impairment
8.7
Renal Impairment
10
OVERDOSAGE
11
DESCRIPTION
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
12.2
Pharmacodynamics
12.3
Pharmacokinetics
13
NONCLINICAL TOXICOLOGY
Version Date 20-Dec-2013
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
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2
Animal Toxicology
14
CLINICAL STUDIES
14.1
Treatment of Osteoporosis in Postmenopausal Women
14.2
Treatment to Increase Bone Mass in Men with Primary or 
Hypogonadal Osteoporosis
14.3
Treatment of Men and Women with Glucocorticoid-Induced 
Osteoporosis
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
16.2
Storage and Handling
17
PATIENT COUNSELING INFORMATION
17.1
Potential Risk of Osteosarcoma and Voluntary FORTEO Patient 
Registry
17.2
Orthostatic Hypotension
17.3
Hypercalcemia
17.4
Other Osteoporosis Treatment Modalities
17.5
Use of Delivery Device
17.6
Availability of Medication Guide and User Manual
* Sections or subsections omitted from the full prescribing information are not 
listed
FULL PRESCRIBING INFORMATION
WARNING: POTENTIAL RISK OF OSTEOSARCOMA
In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that 
was dependent on dose and treatment duration. The effect was observed at systemic exposures to teriparatide ranging from 
3 to 60 times the exposure in humans given a 20-mcg dose. Because of the uncertain relevance of the rat osteosarcoma 
finding to humans, prescribe FORTEO® only for patients for whom the potential benefits are considered to outweigh the 
potential risk. FORTEO should not be prescribed for patients who are at increased baseline risk for osteosarcoma 
(including those with Paget’s disease of bone or unexplained elevations of alkaline phosphatase, pediatric and young adult 
patients with open epiphyses, or prior external beam or implant radiation therapy involving the skeleton) [see Warnings 
and Precautions (5.1), Adverse Reactions (6.2), and Nonclinical Toxicology (13.1)].
1
INDICATIONS AND USAGE
1.1
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture
FORTEO is indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a 
history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available 
osteoporosis therapy. In postmenopausal women with osteoporosis, FORTEO reduces the risk of vertebral and nonvertebral fractures
[see Clinical Studies (14.1)].
1.2
Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture
FORTEO is indicated to increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture, 
defined as a history of osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other 
available osteoporosis therapy [see Clinical Studies (14.2)].
1.3
Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture
FORTEO is indicated for the treatment of men and women with osteoporosis associated with sustained systemic 
glucocorticoid therapy (daily dosage equivalent to 5 mg or greater of prednisone) at high risk for fracture, defined as a history of 
osteoporotic fracture, multiple risk factors for fracture, or patients who have failed or are intolerant to other available osteoporosis 
therapy [see Clinical Studies (14.3)].
2
DOSAGE AND ADMINISTRATION
2.1
Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture
The recommended dose is 20 mcg subcutaneously once a day.
2.2
Increase of Bone Mass in Men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture
The recommended dose is 20 mcg subcutaneously once a day.
2.3
Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis at High Risk for Fracture
The recommended dose is 20 mcg subcutaneously once a day.
2.4
Administration
•
FORTEO should be administered as a subcutaneous injection into the thigh or abdominal wall. There are no data 
available on the safety or efficacy of intravenous or intramuscular injection of FORTEO.
•
FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of 
orthostatic hypotension occur [see Warnings and Precautions (5.7)].
Version Date 20-Dec-2013
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
•
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, 
whenever solution and container permit. FORTEO is a clear and colorless liquid. Do not use if solid particles appear or if 
the solution is cloudy or colored.
•
Patients and caregivers who administer FORTEO should receive appropriate training and instruction on the proper use of 
the FORTEO delivery device from a qualified health professional [see Patient Counseling Information (17.5)].
2.5
Treatment Duration
The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for 
more than 2 years during a patient’s lifetime is not recommended.
3
DOSAGE FORMS AND STRENGTHS
Multi-dose prefilled delivery device (pen) for subcutaneous injection containing 28 daily doses of 20 mcg.
4
CONTRAINDICATIONS
Do not use FORTEO in patients with:
•
Hypersensitivity to teriparatide or to any of its excipients. Reactions have included angioedema and anaphylaxis [see 
Adverse Reactions (6.2)].
5
WARNINGS AND PRECAUTIONS
5.1
Osteosarcoma
In male and female rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone tumor) that was 
dependent on dose and treatment duration [see Boxed Warning and Nonclinical Toxicology (13.1)]. FORTEO should not be 
prescribed for patients at increased baseline risk of osteosarcoma.
These include:
•
Paget’s disease of bone. Unexplained elevations of alkaline phosphatase may indicate Paget’s disease of bone.
•
Pediatric and young adult patients with open epiphyses.
•
Prior external beam or implant radiation therapy involving the skeleton. 
Patients should be encouraged to enroll in the voluntary FORTEO Patient Registry, which is designed to collect information 
about any potential risk of osteosarcoma in patients who have taken FORTEO. Enrollment information can be obtained by calling 1-
866-382-6813, or by visiting www.forteoregistry.rti.org
5.2
Treatment Duration
The safety and efficacy of FORTEO have not been evaluated beyond 2 years of treatment. Consequently, use of the drug for 
more than 2 years during a patients’ lifetime is not recommended.
5.3
Bone Metastases and Skeletal Malignancies
Patients with bone metastases or a history of skeletal malignancies should not be treated with FORTEO.
5.4
Metabolic Bone Diseases
Patients with metabolic bone diseases other than osteoporosis should not be treated with FORTEO.
5.5
Hypercalcemia and Hypercalcemic Disorders
FORTEO has not been studied in patients with pre-existing hypercalcemia. These patients should not be treated with 
FORTEO because of the possibility of exacerbating hypercalcemia. Patients known to have an underlying hypercalcemic disorder, 
such as primary hyperparathyroidism, should not be treated with FORTEO.
5.6
Urolithiasis or Pre-existing Hypercalciuria
In clinical trials, the frequency of urolithiasis was similar in patients treated with FORTEO and placebo. However, FORTEO 
has not been studied in patients with active urolithiasis. If active urolithiasis or pre-existing hypercalciuria are suspected, measurement 
of urinary calcium excretion should be considered. FORTEO should be used with caution in patients with active or recent urolithiasis 
because of the potential to exacerbate this condition.
5.7
Orthostatic Hypotension
FORTEO should be administered initially under circumstances in which the patient can sit or lie down if symptoms of 
orthostatic hypotension occur. In short-term clinical pharmacology studies with teriparatide, transient episodes of symptomatic 
orthostatic hypotension were observed in 5% of patients. Typically, an event began within 4 hours of dosing and spontaneously 
resolved within a few minutes to a few hours. When transient orthostatic hypotension occurred, it happened within the first several 
doses, it was relieved by placing the person in a reclining position, and it did not preclude continued treatment.
5.8
Drug Interactions
Hypercalcemia may predispose patients to digitalis toxicity. Because FORTEO transiently increases serum calcium, patients 
receiving digoxin should use FORTEO with caution [see Drug Interactions (7.1) and Clinical Pharmacology (12.3)].
Version Date 20-Dec-2013
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
6
ADVERSE REACTIONS
6.1
Clinical Trials Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies 
of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Treatment of Osteoporosis in Men and Postmenopausal Women
The safety of FORTEO in the treatment of osteoporosis in men and postmenopausal women was assessed in two randomized, 
double-blind, placebo-controlled trials of 1382 patients (21% men, 79% women) aged 28 to 86 years (mean 67 years). The median 
durations of the trials were 11 months for men and 19 months for women, with 691 patients exposed to FORTEO and 691 patients to 
placebo. All patients received 1000 mg of calcium plus at least 400 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 1% in the FORTEO group and 1% in the placebo group. The incidence of serious 
adverse events was 16% in FORTEO patients and 19% in placebo patients. Early discontinuation due to adverse events occurred in 
7% of FORTEO patients and 6% of placebo patients.
Table 1 lists adverse events from the two principal osteoporosis trials in men and postmenopausal women that occurred in 
≥2% of FORTEO-treated and more frequently than placebo-treated patients.
Table 1. Percentage of Patients with Adverse Events Reported by at Least 2% of FORTEO-Treated Patients and in More 
FORTEO-Treated Patients than Placebo-Treated Patients from the Two Principal Osteoporosis Trials in Women and Men
Adverse Events are Shown Without Attribution of Causality
FORTEO
N=691
Placebo
N=691
  Event Classification
(%)
(%)
  Body as a Whole
  Pain
21.3
20.5
  Headache
7.5
7.4
  Asthenia
8.7
6.8
  Neck pain
3.0 
2.7
  Cardiovascular
  Hypertension
7.1 
6.8
  Angina pectoris
2.5
1.6
  Syncope
2.6
1.4
  Digestive System
  Nausea
8.5
6.7
  Constipation
5.4
4.5
  Diarrhea
5.1
4.6
  Dyspepsia
5.2
4.1
  Vomiting
3.0
2.3
  Gastrointestinal disorder
2.3
2.0
  Tooth disorder
2.0
1.3
  Musculoskeletal
  Arthralgia
10.1
8.4
  Leg cramps
2.6
1.3
  Nervous System
  Dizziness
8.0
5.4
  Depression
4.1
2.7
  Insomnia
4.3
3.6
  Vertigo
3.8
2.7
  Respiratory System
  Rhinitis
9.6
8.8
  Cough increased
6.4
5.5
  Pharyngitis
5.5
4.8
  Dyspnea
3.6
2.6
  Pneumonia
3.9
3.3
  Skin and Appendages
Version Date 20-Dec-2013
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
  Rash
4.9
4.5
  Sweating
2.2
1.7
Immunogenicity — In the clinical trial, antibodies that cross-reacted with teriparatide were detected in 3% of women (15/541) 
receiving FORTEO. Generally, antibodies were first detected following 12 months of treatment and diminished after withdrawal of 
therapy. There was no evidence of hypersensitivity reactions or allergic reactions among these patients. Antibody formation did not 
appear to have effects on serum calcium, or on bone mineral density (BMD) response.
Laboratory Findings
Serum Calcium — FORTEO transiently increased serum calcium, with the maximal effect observed at approximately 4 to 
6 hours post-dose. Serum calcium measured at least 16 hours post-dose was not different from pretreatment levels. In clinical trials, 
the frequency of at least 1 episode of transient hypercalcemia in the 4 to 6 hours after FORTEO administration was increased from 2% 
of women and none of the men treated with placebo to 11% of women and 6% of men treated with FORTEO. The number of patients 
treated with FORTEO whose transient hypercalcemia was verified on consecutive measurements was 3% of women and 1% of men.
Urinary Calcium — FORTEO increased urinary calcium excretion, but the frequency of hypercalciuria in clinical trials was 
similar for patients treated with FORTEO and placebo [see Clinical Pharmacology (12.2)].
Serum Uric Acid — FORTEO increased serum uric acid concentrations. In clinical trials, 3% of FORTEO patients had serum 
uric acid concentrations above the upper limit of normal compared with 1% of placebo patients. However, the hyperuricemia did not 
result in an increase in gout, arthralgia, or urolithiasis.
Renal Function — No clinically important adverse renal effects were observed in clinical studies. Assessments included 
creatinine clearance; measurements of blood urea nitrogen (BUN), creatinine, and electrolytes in serum; urine specific gravity and pH; 
and examination of urine sediment.
Studies in Men and Women with Glucocorticoid-Induced Osteoporosis
The safety of FORTEO in the treatment of men and women with glucocorticoid-induced osteoporosis was assessed in a 
randomized, double-blind, active-controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated 
with ≥ 5mg per day prednisone or equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients 
exposed to FORTEO and 214 patients exposed to oral daily bisphosphonate (active control). All patients received 1000 mg of calcium 
plus 800 IU of vitamin D supplementation per day.
The incidence of all cause mortality was 4% in the FORTEO group and 6% in the active control group. The incidence of 
serious adverse events was 21% in FORTEO patients and 18% in active control patients, and included pneumonia (3% FORTEO, 1% 
active control). Early discontinuation because of adverse events occurred in 15% of FORTEO patients and 12% of active control
patients, and included dizziness (2% FORTEO, 0% active control).
Adverse events reported at a higher incidence in the FORTEO group and with at least a 2% difference in FORTEO-treated 
patients compared with active control-treated patients were: nausea (14%, 7%), gastritis (7%, 3%), pneumonia (6%, 3%), dyspnea 
(6%, 3%), insomnia (5%, 1%), anxiety (4%, 1%), and herpes zoster (3%, 1%), respectively.
6.2
Postmarketing Experience
The following adverse reactions have been identified during postapproval use of FORTEO. Because these reactions are 
reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 
causal relationship to drug exposure.
•
Osteosarcoma: Cases of bone tumor and osteosarcoma have been reported rarely in the postmarketing period. The 
causality to FORTEO use is unclear. Long term osteosarcoma surveillance studies are ongoing [see Warnings and 
Precautions (5.1)]
•
Hypercalcemia: Hypercalcemia greater than 13.0 mg/dL has been reported with FORTEO use.
Adverse events reported since market introduction that were temporally (but not necessarily causally) related to FORTEO 
therapy include the following:
•
Allergic Reactions: Anaphylactic reactions, drug hypersensitivity, angioedema, urticaria
•
Investigations: Hyperuricemia 
•
Respiratory System: Acute dyspnea, chest pain
•
Musculoskeletal: Muscle spasms of the leg or back
•
Other: Injection site reactions including injection site pain, swelling and bruising; oro-facial edema
7
DRUG INTERACTIONS
7.1
Digoxin
A single FORTEO dose did not alter the effect of digoxin on the systolic time interval (from electrocardiographic Q-wave 
onset to aortic valve closure, a measure of digoxin’s calcium-mediated cardiac effect). However, because FORTEO may transiently 
Version Date 20-Dec-2013
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
increase serum calcium, FORTEO should be used with caution in patients taking digoxin [see Warnings and Precaution (5.8) and 
Clinical Pharmacology (12.3)].
7.2
Hydrochlorothiazide
The coadministration of hydrochlorothiazide 25 mg with teriparatide did not affect the serum calcium response to teriparatide 
40 mcg. The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium levels has not been 
studied [see Clinical Pharmacology (12.3)].
7.3
Furosemide
Coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg in healthy people and patients with mild, 
moderate, or severe renal impairment (CrCl 13 to 72 mL/min) resulted in small increases in the serum calcium (2%) and 24-hour urine 
calcium (37%) responses to teriparatide that did not appear to be clinically important [see Clinical Pharmacology (12.3)].
8
USE IN SPECIFIC POPULATIONS
8.1
Pregnancy
Pregnancy Category C — There are no adequate and well-controlled studies of FORTEO in pregnant women. In animal 
studies, teriparatide increased skeletal deviations and variations in mouse offspring at doses more than 60 times the equivalent human 
dose and produced mild growth retardation and reduced motor activity in rat offspring at doses more than 120 times the equivalent 
human dose. FORTEO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
In animal studies, pregnant mice received teriparatide during organogenesis at subcutaneous doses 8 to 267 times the human 
dose. At doses ≥ 60 times the human dose, the fetuses showed an increased incidence of skeletal deviations or variations (interrupted 
rib, extra vertebra or rib). When pregnant rats received subcutaneous teriparatide during organogenesis at doses 16 to 540 times the 
human dose, the fetuses showed no abnormal findings.
In a perinatal/postnatal study, pregnant rats received subcutaneous teriparatide from organogenesis through lactation. Mild 
growth retardation in female offspring at doses ≥120 times the human dose (based on surface area, mcg/m2). Mild growth retardation
in male offspring and reduced motor activity in both male and female offspring occurred at maternal doses 540 times the human dose. 
There were no developmental or reproductive effects in mice or rats at doses 8 or 16 times the human dose, respectively.
Exposure multiples were normalized based on body surface area (mcg/m2). Actual animal doses: mice (30 to 
1000 mcg/kg/day); rats (30 to 1000 mcg/kg/day).
8.3
Nursing Mothers
It is not known whether teriparatide is excreted in human milk. Because of the potential for tumorigenicity shown for 
teriparatide in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account 
the importance of the drug to the mother.
8.4
Pediatric Use
The safety and efficacy of FORTEO have not been established in any pediatric population. FORTEO should not be prescribed 
in patients at an increased baseline risk of osteosarcoma which include pediatric and young adult patients with open epiphyses. 
Therefore, FORTEO is not indicated for use in pediatric or young adult patients with open epiphyses [see Warnings and Precautions
(5.1)].
8.5
Geriatric Use
Of the patients receiving FORTEO in the osteoporosis trial of 1637 postmenopausal women, 75% were 65 years of age and 
over and 23% were 75 years of age and over. Of the patients receiving FORTEO in the osteoporosis trial of 437 men, 39% were 
65 years of age and over and 13% were 75 years of age and over. No overall differences in safety or effectiveness were observed 
between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses 
between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
8.6
Hepatic Impairment
No studies have been performed in patients with hepatic impairment. [see Clinical Pharmacology (12.3)].
8.7
Renal Impairment
In 5 patients with severe renal impairment (CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 
77%, respectively. Maximum serum concentration of teriparatide was not increased [see Clinical Pharmacology (12.3)].
10
OVERDOSAGE
Incidents of overdose in humans have not been reported in clinical trials. Teriparatide has been administered in single doses of 
up to 100 mcg and in repeated doses of up to 60 mcg/day for 6 weeks. The effects of overdose that might be expected include a 
delayed hypercalcemic effect and risk of orthostatic hypotension. Nausea, vomiting, dizziness, and headache might also occur.
In postmarketing spontaneous reports, there have been cases of medication errors in which the entire contents (up to 800 mcg) 
of the FORTEO delivery device (pen) have been administered as a single dose. Transient events reported have included nausea, 
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weakness/lethargy and hypotension. In some cases, no adverse events occurred as a result of the overdose. No fatalities associated 
with overdose have been reported.
Overdose Management — There is no specific antidote for teriparatide. Treatment of suspected overdose should include 
discontinuation of FORTEO, monitoring of serum calcium and phosphorus, and implementation of appropriate supportive measures,
such as hydration.
11
DESCRIPTION
FORTEO (teriparatide [rDNA origin] injection) contains recombinant human parathyroid hormone (1-34), and is also called 
rhPTH (1-34). It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid 
human parathyroid hormone.
Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:
Teriparatide (rDNA origin) is manufactured using a strain of Escherichia coli modified by recombinant DNA technology. 
FORTEO is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a disposable 
delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled with 2.7 mL to deliver 2.4 mL. Each mL 
contains 250 mcg teriparatide (corrected for acetate, chloride, and water content), 0.41 mg glacial acetic acid, 0.1 mg sodium acetate 
(anhydrous), 45.4 mg mannitol, 3 mg Metacresol, and Water for Injection. In addition, hydrochloric acid solution 10% and/or sodium 
hydroxide solution 10% may have been added to adjust the product to pH 4.
Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.
12
CLINICAL PHARMACOLOGY
12.1
Mechanism of Action
Endogenous 84-amino acid parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone 
and kidney. Physiological actions of PTH include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, 
and intestinal calcium absorption. The biological actions of PTH and teriparatide are mediated through binding to specific high-
affinity cell-surface receptors. Teriparatide and the 34 N-terminal amino acids of PTH bind to these receptors with the same affinity 
and have the same physiological actions on bone and kidney. Teriparatide is not expected to accumulate in bone or other tissues.
The skeletal effects of teriparatide depend upon the pattern of systemic exposure. Once-daily administration of teriparatide 
stimulates new bone formation on trabecular and cortical (periosteal and/or endosteal) bone surfaces by preferential stimulation of 
osteoblastic activity over osteoclastic activity. In monkey studies, teriparatide improved trabecular microarchitecture and increased 
bone mass and strength by stimulating new bone formation in both cancellous and cortical bone. In humans, the anabolic effects of 
teriparatide manifest as an increase in skeletal mass, an increase in markers of bone formation and resorption, and an increase in bone 
strength. By contrast, continuous excess of endogenous PTH, as occurs in hyperparathyroidism, may be detrimental to the skeleton 
because bone resorption may be stimulated more than bone formation.
12.2
Pharmacodynamics
Pharmacodynamics in Men and Postmenopausal Women with Osteoporosis
Effects on Mineral Metabolism — Teriparatide affects calcium and phosphorus metabolism in a pattern consistent with the 
known actions of endogenous PTH (e.g., increases serum calcium and decreases serum phosphorus).
Serum Calcium Concentrations — When teriparatide 20 mcg is administered once daily, the serum calcium concentration 
increases transiently, beginning approximately 2 hours after dosing and reaching a maximum concentration between 4 and 6 hours 
(median increase, 0.4 mg/dL). The serum calcium concentration begins to decline approximately 6 hours after dosing and returns to 
baseline by 16 to 24 hours after each dose.
1
5
10
15
20
25
30
Ser
Val Ser
Glu
Ile
Gln Leu Met His Asn
Leu
Gly
Lys
His
Leu
Ser
Met
Glu
Arg
Val
Glu
Trp
Leu
Arg Lys Lys Leu Gln Asp Val His
Phe
Asn
Asn
H-
-OH
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In a clinical study of postmenopausal women with osteoporosis, the median peak serum calcium concentration measured 4 to 
6 hours after dosing with FORTEO (teriparatide 20 mcg) was 2.42 mmol/L (9.68 mg/dL) at 12 months. The peak serum calcium 
remained below 2.76 mmol/L (11.0 mg/dL) in >99% of women at each visit. Sustained hypercalcemia was not observed.
In this study, 11.1% of women treated with FORTEO had at least 1 serum calcium value above the upper limit of normal 
[2.64 mmol/L (10.6 mg/dL)] compared with 1.5% of women treated with placebo. The percentage of women treated with FORTEO 
whose serum calcium was above the upper limit of normal on consecutive 4- to 6-hour post-dose measurements was 3.0% compared 
with 0.2% of women treated with placebo. In these women, calcium supplements and/or FORTEO doses were reduced. The timing of 
these dose reductions was at the discretion of the investigator. FORTEO dose adjustments were made at varying intervals after the 
first observation of increased serum calcium (median 21 weeks). During these intervals, there was no evidence of progressive 
increases in serum calcium.
In a clinical study of men with either primary or hypogonadal osteoporosis, the effects on serum calcium were similar to those 
observed in postmenopausal women. The median peak serum calcium concentration measured 4 to 6 hours after dosing with FORTEO 
was 2.35 mmol/L (9.44 mg/dL) at 12 months. The peak serum calcium remained below 2.76 mmol/L (11.0 mg/dL) in 98% of men at 
each visit. Sustained hypercalcemia was not observed.
In this study, 6.0% of men treated with FORTEO daily had at least 1 serum calcium value above the upper limit of normal 
[2.64 mmol/L (10.6 mg/dL)] compared with none of the men treated with placebo. The percentage of men treated with FORTEO 
whose serum calcium was above the upper limit of normal on consecutive measurements was 1.3% (2 men) compared with none of 
the men treated with placebo. Although calcium supplements and/or FORTEO doses could have been reduced in these men, only 
calcium supplementation was reduced [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)].
In a clinical study of women previously treated for 18 to 39 months with raloxifene (n=26) or alendronate (n=33), mean serum 
calcium >12 hours after FORTEO injection was increased by 0.09 to 0.14 mmol/L (0.36 to 0.56 mg/dL), after 1 to 6 months of 
FORTEO treatment compared with baseline. Of the women pretreated with raloxifene, 3 (11.5%) had a serum calcium >2.76 mmol/L 
(11.0 mg/dL), and of those pretreated with alendronate, 3 (9.1%) had a serum calcium >2.76 mmol/L (11.0 mg/dL). The highest serum 
calcium reported was 3.12 mmol/L (12.5 mg/dL). None of the women had symptoms of hypercalcemia. There were no placebo 
controls in this study.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of FORTEO on serum calcium were similar to 
those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Urinary Calcium Excretion — In a clinical study of postmenopausal women with osteoporosis who received 1000 mg of 
supplemental calcium and at least 400 IU of vitamin D, daily FORTEO increased urinary calcium excretion. The median urinary 
excretion of calcium was 4.8 mmol/day (190 mg/day) at 6 months and 4.2 mmol/day (170 mg/day) at 12 months. These levels were 
0.76 mmol/day (30 mg/day) and 0.3 mmol/day (12 mg/day) higher, respectively, than in women treated with placebo. The incidence 
of hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the women treated with FORTEO or placebo.
In a clinical study of men with either primary or hypogonadal osteoporosis who received 1000 mg of supplemental calcium 
and at least 400 IU of vitamin D, daily FORTEO had inconsistent effects on urinary calcium excretion. The median urinary excretion 
of calcium was 5.6 mmol/day (220 mg/day) at 1 month and 5.3 mmol/day (210 mg/day) at 6 months. These levels were 0.5 mmol/day 
(20 mg/day) higher and 0.2 mmol/day (8.0 mg/day) lower, respectively, than in men treated with placebo. The incidence of 
hypercalciuria (>7.5 mmol Ca/day or 300 mg/day) was similar in the men treated with FORTEO or placebo.
Phosphorus and Vitamin D — In single-dose studies, teriparatide produced transient phosphaturia and mild transient 
reductions in serum phosphorus concentration. However, hypophosphatemia (<0.74 mmol/L or 2.4 mg/dL) was not observed in 
clinical trials with FORTEO.
In clinical trials of daily FORTEO, the median serum concentration of 1,25-dihydroxyvitamin D was increased at 12 months 
by 19% in women and 14% in men, compared with baseline. In the placebo group, this concentration decreased by 2% in women and
increased by 5% in men. The median serum 25-hydroxyvitamin D concentration at 12 months was decreased by 19% in women and 
10% in men compared with baseline. In the placebo group, this concentration was unchanged in women and increased by 1% in men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of FORTEO on serum phosphorus were similar 
to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
Effects on Markers of Bone Turnover — Daily administration of FORTEO to men and postmenopausal women with 
osteoporosis in clinical studies stimulated bone formation, as shown by increases in the formation markers serum bone-specific 
alkaline phosphatase (BSAP) and procollagen I carboxy-terminal propeptide (PICP). Data on biochemical markers of bone turnover 
were available for the first 12 months of treatment. Peak concentrations of PICP at 1 month of treatment were approximately 41% 
above baseline, followed by a decline to near-baseline values by 12 months. BSAP concentrations increased by 1 month of treatment 
and continued to rise more slowly from 6 through 12 months. The maximum increases of BSAP were 45% above baseline in women 
and 23% in men. After discontinuation of therapy, BSAP concentrations returned toward baseline. The increases in formation markers 
were accompanied by secondary increases in the markers of bone resorption: urinary N-telopeptide (NTX) and urinary 
deoxypyridinoline (DPD), consistent with the physiological coupling of bone formation and resorption in skeletal remodeling. 
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Changes in BSAP, NTX, and DPD were lower in men than in women, possibly because of lower systemic exposure to teriparatide in 
men.
In the study of patients with glucocorticoid-induced osteoporosis, the effects of FORTEO on serum markers of bone turnover 
were similar to those observed in postmenopausal women with osteoporosis not taking glucocorticoids.
12.3
Pharmacokinetics
Absorption — Teriparatide is absorbed after subcutaneous injection; the absolute bioavailability is approximately 95% based 
on pooled data from 20-, 40-, and 80- mcg doses. The rates of absorption and elimination are rapid. The peptide reaches peak serum 
concentrations about 30 minutes after subcutaneous injection of a 20-mcg dose and declines to non-quantifiable concentrations within 
3 hours.
Distribution — Systemic clearance of teriparatide (approximately 62 L/hr in women and 94 L/hr in men) exceeds the rate of 
normal liver plasma flow, consistent with both hepatic and extra-hepatic clearance. Volume of distribution, following intravenous 
injection, is approximately 0.12 L/kg. Intersubject variability in systemic clearance and volume of distribution is 25% to 50%. The 
half-life of teriparatide in serum is 5 minutes when administered by intravenous injection and approximately 1 hour when 
administered by subcutaneous injection. The longer half-life following subcutaneous administration reflects the time required for 
absorption from the injection site.
Metabolism and Excretion — No metabolism or excretion studies have been performed with teriparatide. However, the 
mechanisms of metabolism and elimination of PTH(1-34) and intact PTH have been extensively described in published literature. 
Peripheral metabolism of PTH is believed to occur by non-specific enzymatic mechanisms in the liver followed by excretion via the 
kidneys.
Pediatric Patients — Pharmacokinetic data in pediatric patients are not available [see Warnings and Precautions (5.1)].
Geriatric Patients — No age-related differences in teriparatide pharmacokinetics were detected (range 31 to 85 years).
Gender — Although systemic exposure to teriparatide was approximately 20% to 30% lower in men than women, the 
recommended dose for both genders is 20 mcg/day.
Race — The populations included in the pharmacokinetic analyses were 98.5% Caucasian. The influence of race has not been 
determined.
Renal Impairment — No pharmacokinetic differences were identified in 11 patients with mild or moderate renal impairment
[creatinine clearance (CrCl) 30 to 72 mL/min] administered a single dose of teriparatide. In 5 patients with severe renal impairment
(CrCl<30 mL/min), the AUC and T1/2 of teriparatide were increased by 73% and 77%, respectively. Maximum serum concentration of 
teriparatide was not increased. No studies have been performed in patients undergoing dialysis for chronic renal failure [see Use in 
Specific Populations (8.7)].
Hepatic Impairment — No studies have been performed in patients with hepatic impairment.  Non-specific proteolytic 
enzymes in the liver (possibly Kupffer cells) cleave PTH(1-34) and PTH(1-84) into fragments that are cleared from the circulation 
mainly by the kidney [see Use in Specific Populations (8.6)].
Drug Interactions
Digoxin — In a study of 15 healthy people administered digoxin daily to steady state, a single FORTEO dose did not alter the 
effect of digoxin on the systolic time interval (from electrocardiographic Q-wave onset to aortic valve closure, a measure of digoxin’s 
calcium-mediated cardiac effect). However, sporadic case reports have suggested that hypercalcemia may predispose patients to 
digitalis toxicity. Because FORTEO may transiently increase serum calcium, FORTEO should be used with caution in patients taking 
digoxin [see Drug Interactions (7.1)].
Hydrochlorothiazide — In a study of 20 healthy people, the coadministration of hydrochlorothiazide 25 mg with teriparatide 
did not affect the serum calcium response to teriparatide 40 mcg. The 24-hour urine excretion of calcium was reduced by a clinically 
unimportant amount (15%). The effect of coadministration of a higher dose of hydrochlorothiazide with teriparatide on serum calcium 
levels has not been studied [see Drug Interactions (7.2)].
Furosemide — In a study of 9 healthy people and 17 patients with mild, moderate, or severe renal impairment (CrCl 13 to 
72 mL/min), coadministration of intravenous furosemide (20 to 100 mg) with teriparatide 40 mcg resulted in small increases in the 
serum calcium (2%) and 24-hour urine calcium (37%) responses to teriparatide that did not appear to be clinically important [see Drug 
Interactions (7.3)].
13
NONCLINICAL TOXICOLOGY
13.1
Carcinogenesis, Mutagenesis, Impairment of Fertility
Carcinogenesis — Two carcinogenicity bioassays were conducted in Fischer 344 rats. In the first study, male and female rats 
were given daily subcutaneous teriparatide injections of 5, 30, or 75 mcg/kg/day for 24 months from 2 months of age. These doses 
resulted in systemic exposures that were, respectively, 3, 20, and 60 times higher than the systemic exposure observed in humans 
following a subcutaneous dose of 20 mcg (based on AUC comparison). Teriparatide treatment resulted in a marked dose-related 
increase in the incidence of osteosarcoma, a rare malignant bone tumor, in both male and female rats. Osteosarcomas were observed at 
all doses and the incidence reached 40% to 50% in the high-dose groups. Teriparatide also caused a dose-related increase in 
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osteoblastoma and osteoma in both sexes. No osteosarcomas, osteoblastomas or osteomas were observed in untreated control rats. The 
bone tumors in rats occurred in association with a large increase in bone mass and focal osteoblast hyperplasia.
The second 2-year study was carried out in order to determine the effect of treatment duration and animal age on the 
development of bone tumors. Female rats were treated for different periods between 2 and 26 months of age with subcutaneous doses 
of 5 and 30 mcg/kg (equivalent to 3 and 20 times the human exposure at the 20-mcg dose, based on AUC comparison). The study 
showed that the occurrence of osteosarcoma, osteoblastoma and osteoma was dependent upon dose and duration of exposure. Bone 
tumors were observed when immature 2-month old rats were treated with 30 mcg/kg/day for 24 months or with 5 or 30 mcg/kg/day 
for 6 months. Bone tumors were also observed when mature 6-month old rats were treated with 30 mcg/kg/day for 6 or 20 months. 
Tumors were not detected when mature 6-month old rats were treated with 5 mcg/kg/day for 6 or 20 months. The results did not 
demonstrate a difference in susceptibility to bone tumor formation, associated with teriparatide treatment, between mature and 
immature rats.
The relevance of these animal findings to humans is uncertain.
Mutagenesis — Teriparatide was not genotoxic in any of the following test systems: the Ames test for bacterial mutagenesis; 
the mouse lymphoma assay for mammalian cell mutation; the chromosomal aberration assay in Chinese hamster ovary cells, with and 
without metabolic activation; and the in vivo micronucleus test in mice.
Impairment of Fertility — No effects on fertility were observed in male and female rats given subcutaneous teriparatide doses 
of 30, 100, or 300 mcg/kg/day prior to mating and in females continuing through gestation Day 6 (16 to 160 times the human dose of 
20 mcg based on surface area, mcg/m2).
13.2
Animal Toxicology 
In single-dose rodent studies using subcutaneous injection of teriparatide, no mortality was seen in rats given doses of 
1000 mcg/kg (540 times the human dose based on surface area, mcg/m2) or in mice given 10,000 mcg/kg (2700 times the human dose 
based on surface area, mcg/m2).
In a long-term study, skeletally mature ovariectomized female monkeys (N=30 per treatment group) were given either daily 
subcutaneous teriparatide injections of 5 mcg/kg or vehicle. Following the 18-month treatment period, the monkeys were removed 
from teriparatide treatment and were observed for an additional 3 years. The 5 mcg/kg dose resulted in systemic exposures that were 
approximately 6 times higher than the systemic exposure observed in humans following a subcutaneous dose of 20 mcg (based on 
AUC comparison). Bone tumors were not detected by radiographic or histologic evaluation in any monkey in the study.
14
CLINICAL STUDIES
14.1
Treatment of Osteoporosis in Postmenopausal Women
The safety and efficacy of once-daily FORTEO, median exposure of 19 months, were examined in a double-blind, 
multicenter, placebo-controlled clinical study of 1637 postmenopausal women with osteoporosis (FORTEO 20 mcg, n=541).
All women received 1000 mg of calcium and at least 400 IU of vitamin D per day. Baseline and endpoint spinal radiographs 
were evaluated using the semiquantitative scoring. Ninety percent of the women in the study had 1 or more radiographically diagnosed 
vertebral fractures at baseline. The primary efficacy endpoint was the occurrence of new radiographically diagnosed vertebral 
fractures defined as changes in the height of previously undeformed vertebrae. Such fractures are not necessarily symptomatic.
Effect on Fracture Incidence
New Vertebral Fractures — FORTEO, when taken with calcium and vitamin D and compared with calcium and vitamin D 
alone, reduced the risk of 1 or more new vertebral fractures from 14.3% of women in the placebo group to 5.0% in the FORTEO 
group. This difference was statistically significant (p<0.001); the absolute reduction in risk was 9.3% and the relative reduction was 
65%. FORTEO was effective in reducing the risk for vertebral fractures regardless of age, baseline rate of bone turnover, or baseline 
BMD (see Table 2).
Table 2. Effect of FORTEO on Risk of Vertebral Fractures in Postmenopausal Women with Osteoporosis
Percent of Women With Fracture
FORTEO
(N=444)
Placebo
(N=448)
Absolute Risk Reduction
(%, 95% CI)
Relative Risk Reduction
(%, 95% CI)
New fracture (≥1)
5.0a
14.3
9.3 (5.5-13.1)
65 (45-78)
1 fracture
3.8
9.4
2 fractures
0.9
2.9
≥3 fractures
0.2
2.0
a
p≤0.001 compared with placebo.
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New Nonvertebral Osteoporotic Fractures — FORTEO significantly reduced the risk of any nonvertebral fracture from 5.5% 
in the placebo group to 2.6% in the FORTEO group (p<0.05). The absolute reduction in risk was 2.9% and the relative reduction was 
53%. The incidence of new nonvertebral fractures in the FORTEO group compared with the placebo group was ankle/foot (0.2%, 
0.7%), hip (0.2%, 0.7%), humerus (0.4%, 0.4%), pelvis (0%, 0.6%), ribs (0.6%, 0.9%), wrist (0.4%, 1.3%), and other sites (1.1%, 
1.5%), respectively.
The cumulative percentage of postmenopausal women with osteoporosis who sustained new nonvertebral fractures was lower 
in women treated with FORTEO than in women treated with placebo (see Figure 1).
Figure 1. Cumulative Percentage of Postmenopausal Women with Osteoporosis Sustaining New Nonvertebral 
Osteoporotic Fractures
Effect on Bone Mineral Density (BMD)
FORTEO increased lumbar spine BMD in postmenopausal women with osteoporosis. Statistically significant increases were 
seen at 3 months and continued throughout the treatment period. Postmenopausal women with osteoporosis who were treated with 
FORTEO had statistically significant increases in BMD from baseline to endpoint at the lumbar spine, femoral neck, total hip, and 
total body (see Table 3).
Table 3. Mean Percent Change in BMD from Baseline to Endpointa in Postmenopausal Women with Osteoporosis, Treated 
with FORTEO or Placebo for a Median of 19 Months
FORTEO
N=541
Placebo
N=544
Lumbar spine BMD
9.7b
1.1
Femoral neck BMD
2.8c
-0.7
Total hip BMD
2.6c
-1.0
Trochanter BMD
3.5c
-0.2
Intertrochanter BMD
2.6c
-1.3
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Ward’s triangle BMD
4.2c
-0.8
Total body BMD
0.6c
-0.5
Distal 1/3 radius BMD
-2.1
-1.3
Ultradistal radius BMD
-0.1
-1.6
a
Intent-to-treat analysis, last observation carried forward.
b
p<0.001 compared with placebo.
c
p<0.05 compared with placebo.
FORTEO treatment increased lumbar spine BMD from baseline in 96% of postmenopausal women treated. 
Seventy-two percent of patients treated with FORTEO achieved at least a 5% increase in spine BMD, and 44% gained 10% or more.
Both treatment groups lost height during the trial. The mean decreases were 3.61 and 2.81 mm in the placebo and FORTEO 
groups, respectively.
Bone Histology
The effects of teriparatide on bone histology were evaluated in iliac crest biopsies of 35 postmenopausal women treated for 
12 to 24 months with calcium and vitamin D and teriparatide 20 or 40 mcg/day. Normal mineralization was observed with no evidence 
of cellular toxicity. The new bone formed with teriparatide was of normal quality (as evidenced by the absence of woven bone and 
marrow fibrosis).
14.2
Treatment to Increase Bone Mass in Men with Primary or Hypogonadal Osteoporosis
The safety and efficacy of once-daily FORTEO, median exposure of 10 months, were examined in a double-blind, 
multicenter, placebo-controlled clinical study of 437 men with either primary (idiopathic) or hypogonadal osteoporosis (FORTEO 
20 mcg, n=151). All men received 1000 mg of calcium and at least 400 IU of vitamin D per day. The primary efficacy endpoint was 
change in lumbar spine BMD.
FORTEO increased lumbar spine BMD in men with primary or hypogonadal osteoporosis. Statistically significant increases 
were seen at 3 months and continued throughout the treatment period. FORTEO was effective in increasing lumbar spine BMD 
regardless of age, baseline rate of bone turnover, and baseline BMD. The effects of FORTEO at additional skeletal sites are shown in 
Table 4.
FORTEO treatment for a median of 10 months increased lumbar spine BMD from baseline in 94% of men treated. 
Fifty-three percent of patients treated with FORTEO achieved at least a 5% increase in spine BMD, and 14% gained 10% or more.
Table 4. Mean Percent Change in BMD from Baseline to Endpointa in Men with Primary or Hypogonadal Osteoporosis, 
Treated with FORTEO or Placebo for a Median of 10 Months
FORTEO
N=151
Placebo
N=147
Lumbar spine BMD
5.9b
0.5
Femoral neck BMD
1.5c
0.3
Total hip BMD
1.2
0.5
Trochanter BMD
1.3
1.1
Intertrochanter BMD
1.2
0.6
Ward’s triangle BMD
2.8
1.1
Total body BMD
0.4
-0.4
Distal 1/3 radius BMD
-0.5
-0.2
Ultradistal radius BMD
-0.5
-0.3
a
Intent-to-treat analysis, last observation carried forward.
b
p<0.001 compared with placebo.
c
p<0.05 compared with placebo.
14.3
Treatment of Men and Women with Glucocorticoid-Induced Osteoporosis
The efficacy of FORTEO for treating glucocorticoid-induced osteoporosis was assessed in a randomized, double-blind, active-
controlled trial of 428 patients (19% men, 81% women) aged 22 to 89 years (mean 57 years) treated with ≥5 mg/day prednisone or 
equivalent for a minimum of 3 months. The duration of the trial was 18 months with 214 patients exposed to FORTEO. In the 
FORTEO group, the baseline median glucocorticoid dose was 7.5 mg/day and the median duration of glucocorticoid use was 1.5
years. The mean (SD) baseline lumbar spine BMD was 0.85 ± 0.13 g/cm2 and lumbar spine BMD T-score was –2.5 ± 1 (number of 
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standard deviations below the mean BMD value for healthy adults). A total of 30% of patients had prevalent vertebral fracture(s) and 
43% had prior non-vertebral fracture(s). The patients had chronic rheumatologic, respiratory or other diseases that required sustained 
glucocorticoid therapy. All patients received 1000 mg of calcium plus 800 IU of vitamin D supplementation per day. 
Because of differences in mechanism of action (anabolic vs. anti-resorptive) and lack of clarity regarding differences in BMD 
as an adequate predictor of fracture efficacy, data on the active comparator are not presented. 
Effect on Bone Mineral Density (BMD)
In patients with glucocorticoid-induced osteoporosis, FORTEO increased lumbar spine BMD compared with baseline at 3 
months through 18 months of treatment. In patients treated with FORTEO, the mean percent change in BMD from baseline to 
endpoint was 7.2% at the lumbar spine, 3.6% at the total hip, and 3.7% at the femoral neck (p<0.001 all sites). The relative treatment 
effects of FORTEO were consistent in subgroups defined by gender, age, geographic region, body mass index, underlying disease, 
prevalent vertebral fracture, baseline glucocorticoid dose, prior bisphosphonate use, and glucocorticoid discontinuation during trial.
16
HOW SUPPLIED/STORAGE AND HANDLING
16.1
How Supplied
The FORTEO delivery device (pen) is available in the following package size:
•
2.4 mL prefilled delivery device NDC 0002-8400-01 (MS8400).
16.2
Storage and Handling
•
The FORTEO delivery device should be stored under refrigeration at 2° to 8°C (36° to 46°F) at all times.
•
Recap the delivery device when not in use to protect the cartridge from physical damage and light.
•
During the use period, time out of the refrigerator should be minimized; the dose may be delivered immediately following 
removal from the refrigerator.
•
Do not freeze. Do not use FORTEO if it has been frozen.
17
PATIENT COUNSELING INFORMATION
See Medication Guide.
17.1
Potential Risk of Osteosarcoma and Voluntary FORTEO Patient Registry
Patients should be made aware that in rats, teriparatide caused an increase in the incidence of osteosarcoma (a malignant bone 
tumor) that was dependent on dose and treatment duration. Patients should be encouraged to enroll in the voluntary FORTEO Patient 
Registry, which is designed to collect information about any potential risk of osteosarcoma in patients who have taken FORTEO.  
Enrollment information can be obtained by calling 1-866-382-6813, or by visiting www.forteoregistry.rti.org.
17.2
Orthostatic Hypotension
FORTEO should be administered initially under circumstances where the patient can immediately sit or lie down if symptoms 
occur. Patients should be instructed that if they feel lightheaded or have palpitations after the injection, they should sit or lie down 
until the symptoms resolve. If symptoms persist or worsen, patients should be instructed to consult a physician before continuing 
treatment [see Warnings and Precautions (5.7)].
17.3
Hypercalcemia
Although symptomatic hypercalcemia was not observed in clinical trials, physicians should instruct patients taking FORTEO 
to contact a health care provider if they develop persistent symptoms of hypercalcemia (e.g., nausea, vomiting, constipation, lethargy, 
muscle weakness).
17.4
Other Osteoporosis Treatment Modalities
Patients should be informed regarding the roles of supplemental calcium and/or vitamin D, weight-bearing exercise, and 
modification of certain behavioral factors such as cigarette smoking and/or alcohol consumption.
17.5
Use of Delivery Device (Pen)
Patients and caregivers who administer FORTEO should be instructed on how to properly use the delivery device (refer to 
User Manual), properly dispose of needles, and be advised not to share their delivery device with other patients. The contents of the 
delivery device should NOT be transferred to a syringe.
Each FORTEO delivery device can be used for up to 28 days including the first injection from the delivery device. After the 
28-day use period, discard the FORTEO delivery device, even if it still contains some unused solution.
17.6
Availability of Medication Guide and User Manual
Patients should read the Medication Guide and delivery device (pen) User Manual before starting therapy with FORTEO and 
re-read them each time the prescription is renewed. Patients need to understand and follow the instructions in the FORTEO delivery 
device User Manual. Failure to do so may result in inaccurate dosing. 
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
Literature revised: March 21, 2012
Marketed by: Lilly USA, LLC
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PA097FSAM01
Version Date 20-Dec-2013
Page 70 of 72


24.14 Blood Draw Amounts 
Version Date 20-Dec-2013
Page 71 of 72


Screening
V0
V1
V2
V3
V4
V5
V6
V7
V8
V9
V10
V11
Cumulative
mls
2Ͳ6
weeks
Month
0
Month
6
Month
12
Month
18
Month
24
Month
30
Month
36
Month
42
Month
48
Month
54
Month
60
Month
66
BloodTests
DNATestingͲifindicated
(notincludedinprotocol)
Chem20(4ml)
4
4
4
4
4
4
4
4
4
4
4
4
4
52
Completebloodcount
(3ml)
3
3
3
3
3
3
3
3
3
3
3
3
3
39
Mineralpanelorcalcium
level(4ml)Ͳasneeded
8
32
4
4
4
4
4
4
4
4
4
4
4
84
ThyroidPanel(4ml)
4
4
4
4
4
4
4
4
4
4
4
4
4
52
25ͲOHͲVitD(5ml)
5
5
5
5
5
5
5
5
5
5
5
5
5
65
1,25(OH)2(4ml)
4
4
4
4
4
4
4
4
4
4
4
4
4
52
IntactPTH(3ml)
3
3
3
3
3
3
3
3
3
3
3
3
3
39
BSAP(4ml)
4
4
4
4
4
4
4
4
4
4
4
4
48
Osteocalcin(3ml)
3
3
3
3
3
3
3
3
3
3
3
3
36
Ionizedcalcium
(1ml)
1
1
1
1
1
1
1
1
1
1
1
1
1
13
ResearchBloodforsample
storage
(4ml)
4
4
4
4
4
4
4
4
4
4
4
4
48
24Ͳhrbloodsampling
(4mlsX13=52ml)
52
52
Acutecareandmineral
panelsforday1at8am,
12pm,4pm,8pm,
8amonday2
20
20
FGFͲ23(4ml)
4
4
Total(ml)
32
91
39
91
39
39
39
39
39
39
39
39
39
604
604
07ͲDͲ0016BloodDrawAmounts
Versiondate:09Apr2013
Version Date 20-Dec-2013
Page 72 of 72


 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
 •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Institute of Dental and Craniofacial Research 
 
 
STUDY NUMBER: 
07-D-0016 
PRINCIPAL INVESTIGATOR: Rachel I. Gafni, M.D.  
 
 
STUDY TITLE: 
Effects of PTH Replacement on Bone in Hypoparathyroidism 
 
 
Continuing Review Approved by the IRB on 03/25/15 
Amendment Approved by the IRB on 09/11/15 (Z)  
 
 
 
Date Posted to Web:  09/17/15 
Standard  
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
First, we want you to know that: 
Taking part in NIH research is entirely voluntary. 
You may choose not to take part, or you may withdraw from the study at any time.  In either case, you will not 
lose any benefits to which you are otherwise entitled.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
You may receive no benefit from taking part.  The research may give us knowledge that may help people in the 
future. 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions).  If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to the study. 
Now we will describe this research study.  Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other 
health professional. 
 
Purpose of the Study 
The purpose of this study is to see how treatment with parathyroid hormone (PTH) affects bones of people with 
hypoparathyroidism.  
Background 
You have a disorder called hypoparathyroidism. People with this disorder do not make enough PTH. PTH is a hormone 
made by the parathyroid glands, which are located in the neck. Sometimes, hypoparathyroidism starts during childhood.  
It can also begin later in life. If it begins later, it is usually due to damage or removal of the parathyroid glands during 
surgery. 
PTH helps control the amount of calcium in blood, kidneys, and bones. When there is not enough PTH, the calcium level 
in the blood can be too low and the level in the kidneys, urine, and bones can be too high. Low levels of calcium in the 
blood can cause a person to feel sick. It can cause cramping or tingling in the hands, feet, or other parts of the body. A 
very low blood calcium can cause fainting or seizures. The standard treatment for hypoparathyroidism is a form of vitamin 
D (usually calcitriol) and calcium supplements. Most patients take these medications by mouth several times a day. 
Calcitriol helps the body absorb calcium from the supplements and food. Keeping blood calcium levels normal can be 


 
 
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STUDY NUMBER: 
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CONTINUATION: Page 2 of 10 pages 
 
 
 
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difficult and sometimes impossible. Sometimes there is too much calcium in the urine even if the calcium levels in the 
blood are low. High calcium in the kidneys and urine can cause problems such as calcium deposits in the kidney 
(nephrocalcinosis) or kidney stones. High levels of calcium in the kidney may keep the kidney from functioning normally.  
There is a manufactured form of PTH that is similar to the hormone that the body makes. Unlike calcitriol, PTH must be 
given as a shot under the skin using a small needle. Previous research has shown that PTH may improve calcium levels in 
blood and urine. However, how PTH affects the bones of people with hypoparathyroidism is not well understood. This 
study will examine the effects of PTH treatment on bone in people with hypoparathyroidism. 
Study Population 
This study will enroll about 36 people with hypoparathyroidism. 
 
Who Can Be In This Study 
You may be eligible to participate if you: 
1. Have had hypoparathyroidism for at least one year.  
2. Are a man between 18-70 years old at the first visit; 
3. Are a woman between 18-45 years old and have not started menopause at the first visit. Or are a woman 
between 53-70 years old and have not had a menstrual cycle within the past 5 years.    
 
 
Who May Not Be In This Study 
You may not be eligible to be in this study if you: 
 
1. Have decreased liver or kidney function 
2. Have allergy or inability to take certain types of antibiotics (such as tetracycline) 
3. Are pregnant or nursing, or if you are planning to become pregnant during the course of the study.  Women 
who are able to get pregnant must agree to use an effective form of birth control while in this study. 
4. Are in menopause or are starting menopause  
5. Have another disease or condition that may affect bone, such as diabetes, celiac disease, Crohn’s disease, 
Cushing syndrome, or adrenal insufficiency.  
6. Have active thyroid cancer and/or are receiving treatment with suppressive doses of thyroid hormone 
7. Have taken medicines or received radiation that affect the bones 
8. Used steroid medicine or estrogen replacement for more than 3 weeks in the past 6 months. 
9. Have uncontrollable low calcium levels requiring frequent intravenous calcium 
10. Are taking medicine for a seizure disorder  
11. Have cancer of the retina  
12. Have a genetic condition that increases your risk for bone cancer. 
13. Have bones that have not stopped growing.  (We’ll check this by an x-ray of your hand). 
14. Have ever had previous treatment with PTH for more than 2 weeks 
 
Procedures 
The study includes 13 visits to the NIH Clinical Center over a 6 year period. Those 13 visits include one inpatient visit for 
tests to see if you can be in the study.  It also includes one baseline inpatient visit, 10 follow-up visits (1 visit about every 
6 months), and one follow-up visit after you have stopped PTH.  Follow-up visits could be inpatient or outpatient. The 
NIH visits vary in length from 1 to 10 days. In between visits, you will also need to have regular blood and urine tests at 
a doctor or laboratory near your home. 


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 3 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Screening Period 
For the first visit you will be admitted to the NIH clinical Center for 2-3 days. We will do tests to see if you qualify for the 
study. If you qualify and agree to participate, you will be placed on calcium and calcitriol.  You will take calcium and 
calcitriol for 1-7 months before your first dose of PTH.   Your return visit will be scheduled at your convenience. 
Baseline Visit 
This baseline visit will occur after the doses of calcium and calcitriol are stable.  This inpatient visit at the NIH Clinical 
Center may last 7 – 10 days.  At this visit you will start taking PTH. You will take PTH twice a day for up to 5 years. You 
will take PTH by shot. You will be taught how to give yourself a shot under the skin using a small needle.  At this visit you 
will have a bone biopsy from your hip.  The month before the biopsy, you will be given antibiotics to take for a few days.  
Follow-up Visits 
You will come to the NIH for a follow-up visit every 6 months while you are taking PTH. One follow-up visit will occur 
after you stop taking PTH. The follow-up visit with the bone biopsy will be inpatient and will last 5-7 days.  Other follow-
up visit will last 1-3 days and may be inpatient or outpatient. The purpose of these visits is to run tests and to make sure 
your PTH dose is correct. We may also adjust your other medications or add medications based on the results of the 
blood and urine tests. 
During one of those follow-up visits, you will have a second bone biopsy taken from the other hip. That second biopsy will 
be done after 1 year, 2 years, or 4 years of taking PTH. The timing of the second biopsy will be determined randomly. 
Doing this in a random way makes the scientific information we get from the biopsies more accurate. The month before 
the biopsy, you will be given antibiotics to take for a few days. 
 
Research Test Procedures 
This section details the procedures and assessments that will be completed.  The section also clarifies at which visits the 
procedures will be done. 
1. Medical History, Vital Signs and Physical Exam.  (Each study visit) The study doctor will ask you about 
your health, check your vital signs such as heart rate and blood pressure, temperature, and breathing rate.  
You will also have a physical exam. These will take about 60-90 minutes. 
2. Blood tests. (Each study visit) Blood will be drawn through a needle in your arm.  We will draw no more than 
2 tablespoons of blood at any one time. You may be asked not to eat after midnight the night before these are 
done.  The total blood drawn during most study visits is approximately 2 tablespoons. 
Blood tests will be used to monitor your safety. Blood will also be drawn for future research.  It may also be 
drawn to test for genetic causes of hypoparathyroidism. You will be asked to sign a separate consent form for 
this test. 
On the day you start taking the PTH shots, you may have up to 4 blood draws throughout the day.   If you 
would like, an intravenous catheter can be placed for the purpose of painless blood draws through the day.   
On subsequent visit days, there will be only one or two blood draws per day.  The total blood drawn during 
the entire Baseline visit will be approximately 6 tablespoons.  


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 4 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Genetic Testing. You may be asked to give 3-5 ml (1 teaspoon) of blood for genetic testing. The genetic 
material, DNA, will be extracted from the sample and analyzed in order to identify the genes causing the 
hypoparathyroidism in your family. 
24-Hour Blood Sampling.  After you have been taking PTH for one year, you will have blood drawn every 2 
hours over a 24-hour period. The purpose is to monitor the changes in different minerals throughout the day 
and night while you are taking PTH. The amount of blood drawn over the 24-hour period will be about 3 
tablespoons. An intravenous catheter will be placed for the purpose of painless blood draws through the day. 
For the IV, a needle will be used to guide a thin plastic tube (catheter) into one of your veins. The needle will 
be removed, leaving only the catheter in the vein. The catheter will be taped to the skin to hold it in place.  
Occasionally, there is difficulty placing the IV and we may need to place a longer catheter called, called a PICC 
line, into one of your larger veins. 
3. Questionnaires. (Screening, Baseline, and Follow-up visits) You will be asked questions about your diet, overall 
health, and feelings of fatigue.  It should take you less than an hour to complete these questionnaires. 
4. 6-Minute Walk Test. (Baseline and Follow-up visits) You will be asked to complete a 6 minute walking test.  For 
the walking test, you will be asked to walk back and forth on an indoor walking course.  You will be asked to walk 
as briskly as is comfortable for you.  The walk will continue for 6 minutes or until you are unable to continue. You 
will be monitored by a rehabilitation specialist throughout the test. 
5. Bone Age X-ray. (Screening Visit) People less than 21 years of age will have a bone age X-ray of the one hand. 
We will use this x-ray to see if your bones have stopped growing. It takes only a few minutes. 
6. Bone Density (DXA) Scan.  (Screening and all follow-up visits) This is an X-ray of your bones to measure bone 
mineral density. For this test, you will lie on an open table while an X-ray machine moves around you.  You will 
only need to stay still for a few minutes at a time.  The test will take about 30 minutes. 
7. CT Scan. (Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5 visits) CT scanning uses x-rays to obtain an image 
of the kidneys and spine.  The CT scanner is shaped like a metal cylinder.  For the CT scan you will lie on a table 
that can slide in an out of the cylinder.  You will in the scanner for about 15 minutes.  You will be able to 
communicate with the CT staff at all times, and you may ask to be moved out of the machine at any time. 
8. Kidney Ultrasound (Baseline, Year 1, Year 2, Year 3, Year 4 and Year 5 visits)  A kidney ultrasound to look for 
calcium deposits.  For this test you will need to lie on a table for about 15-30 minutes while a technician moves a 
wand over your back to look at your kidneys. 
9. 24-hour Urine Collection.  (Each study visit) Collection of urine for 24 hours.    When you are in the Clinical 
Center the container may be stored in the bathroom. A nurse will collect the urine throughout the day.   At other 
times, you will be asked to save and collect your urine for a 24 hour period. 
10. Urine Collection (Baseline visit) Urine samples will be collected 4 times on the day that you start taking PTH 
and then once a day on the following days of this visit. 
11. Urine Pregnancy Test.  (Each study visit) Women who are able to become pregnant will have a pregnancy test 
at each study visit. 
12. Bone Biopsy Procedure.  (Baseline and only once during follow-up) 
You will not have more than 2 biopsies in this study. The biopsy procedure can be uncomfortable. The bone 
biopsy will be done in the operating room.  You will be given some medicine to make you sleepy. This can be 


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 5 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
given as: a pill; a suppository inserted into the rectum; or a shot under the skin, into a muscle, or by injection 
into your vein. The skin over the area of the hip will be cleaned. A numbing medication will be injected with a 
small needle into the skin.  The needle will go through the underlying tissues, and onto the surface of the 
bone. A larger needle, about the width of a pencil (approximately 1/3 inch in diameter), will then be inserted 
through a small skin incision into the bone to remove bone tissue. The skin incision will be closed with several 
stitches that will dissolve within 2-3 weeks.  After the biopsy is over, you will receive additional pain medicine 
as needed. The biopsies will be performed in the operating room by a qualified surgeon with an 
anesthesiologist on hand. The biopsy procedure usually takes less than an hour.  You will be asked to sign a 
separate surgical consent form before the procedure. 
 
The month before each biopsy you will be asked to take an antibiotic. You will take it for 3 days. Then you will 
stop taking it for 12 days.  And then you will take it again for 3 more days. The schedule will be explained to 
you again when it comes time to take the antibiotic. 
13. Tests at Your Local Laboratory 
Between follow-up visits, you will be asked to go to your local laboratory for blood and urine tests. At first, you 
will need blood tests at least once a week. Later, you will need blood tests once a month. You will need urine 
tests every 3 months. You or your local laboratory will send the laboratory results to the study staff. One of 
the study doctors will contact you to adjust your medications, as needed. 
Risks, Inconveniences and Discomforts 
Some of the known risks and discomforts of the study drug and procedures are listed below. As with all studies, there 
may be risks or discomforts we don’t know about. 
PTH 
The PTH used in this study has not been approved by the Food and Drug Administration (FDA). However, Forteo 
(recombinant human PTH), a drug almost identical to the PTH used in this study, has been approved by the FDA for the 
treatment of osteoporosis. Forteo has a proven bone-building effect in elderly people with osteoporosis. The most 
common side effects of Forteo include pain, joint pain, nausea, and high levels of calcium in the blood. 
The known risks of taking PTH for hypoparathyroidism are described below. There may be additional risks from taking 
PTH injections that are not yet known.   
- 
Daily shots of PTH under the skin may cause discomfort. If done properly, using small needles, these shots 
should not be painful. 
- 
Some people may develop bone pain during their PTH therapy. This may be treated with a change in the PTH 
dose.  
- 
PTH shots may cause enlargement of blood vessels in the skin. This may cause redness. 
- 
Some people feel lightheaded or have a decrease in blood pressure, especially with the first dose. This will be 
monitored closely while you are at the NIH. 
- 
Some people, both with osteoporosis or hypoparathyroidism, have decreases in the bone density of the wrist 
while they are taking PTH.  However, there have not been reports of increased wrist fractures in people taking 
PTH.  We will be monitoring your bone density every 6 months.  If your bone density becomes low, you may 
have to stop taking PTH. 


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 6 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
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NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
- 
Some people develop resistance to PTH therapy. This means that the body does not respond to the medicine. 
These people may require gradual increases in PTH dose to keep the calcium levels in the target range. If this 
happens to you, you may be able to continue the therapy if the resistance is mild. Others may develop severe 
resistance and the calcium levels stay dangerously low. If that happens to you, PTH treatment will have to be 
stopped and you will have to go back to taking standard treatment.  
When it is time to take you off PTH, we will gradually decrease the dose to keep your calcium levels where they need to 
be.   We may need to check your blood levels frequently at your local laboratory during that time.  Some people need to 
take higher doses of calcium and calcitriol than they did before joining the study for several months while they are 
switching off of the PTH.  We will monitor you as long as necessary to make sure that your calcium levels are stable off of 
the PTH. 
 
Since this study has started, we have noticed that the amount of citrate in the urine decreases in many patients after they 
start taking PTH.  Some patients have low urine citrate levels even before starting PTH.  Urine citrate helps to prevent 
calcium deposits and kidney stones.  It is not known if the decrease in urine citrate increases the risk of calcium deposits 
in people with hypoparathyroidism, but it might. We will check the citrate level in your urine every time that you do a 24-
hour urine test.  If the level of citrate is not high enough compared to the urine calcium level, we may ask you to take 
potassium citrate pills, an FDA-approved treatment for low urine citrate that is used to prevent kidney stones.  These pills 
may help to protect your kidneys from calcium deposits and kidney stones, even if your urine citrate levels do not become 
completely normal.  The most common side effect of potassium citrate is stomach upset.  If you cannot tolerate the 
potassium citrate tablets, you will not be required to take them. 
  
You should be aware that in animal studies, some rats developed bone cancer after receiving high doses of Forteo. 
However, monkeys given high doses Forteo have not been shown to develop bone tumors. There have been two reports 
of bone cancer in patients treated with Forteo for osteoporosis. However, it is not known whether the Forteo actually 
caused the bone cancer. Over 1,000,000 people have been treated with Forteo around the world. No one knows if there 
is truly an increased risk for cancer, but there is a possibility. The risk of cancer may be greater if PTH is given for a long 
periods of time. As a result, the FDA has issued a warning for Forteo. The warning states that Forteo should not be 
prescribed for people with an increased risk of bone cancer. Those at increased risk include people with certain diseases, 
such as Paget’s disease of bone, a history of radiation therapy to the bones, or a history of bone cancer and children or 
young adults with open growth plates in their bones.  The safety and effectiveness of Forteo has not been established 
beyond two years. 
Blood Draws 
You may have discomfort and bruising at the site of the needle stick. There is a very small risk of fainting.  Infection in 
the area of the needle stick is rare.  
The risks of an intravenous catheter or PICC line include bleeding, infection, or inflammation of the skin and vein with 
pain and swelling.  These will be treated if they occur.  
Drawing blood every 2 hours (at the 1 year visit) may be inconvenient to you and may disrupt your sleep. 
Urine collections 
Urine collections are an inconvenience but do not involve risk. 


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 7 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Walk test 
The 6-minute walk test may make you tired. You can stop if you become too tired.  A rehabilitation specialist will be 
present throughout the test. 
Bone biopsy 
The bone biopsy may cause discomfort and pain for several days. You will be given medicine to help you with the pain. 
The biopsy is performed through a small skin incision. Bleeding and infection at the site of the biopsy are possible but 
rare. The anesthesia used during the biopsy may cause nausea, vomiting or decreased appetite for a day or two after the 
biopsy.  You will need to avoid doing any intense exercise or heavy lifting for about two weeks after the biopsy.  
Antibiotic 
Prior to the biopsy you will take tetracycline or demeclocycline. In some people, these antibiotics may cause nausea, 
vomiting, or diarrhea.   The antibiotics may also make your skin more sensitive to sunlight, so you will need to avoid 
extensive exposure to direct sunlight while taking these antibiotics. 
Radiation 
This research study involves exposure to radiation from annual CT scans and DXA scans every 6 months.  This radiation 
exposure is not required for your medical care and is for research purposes only. The amount of radiation you will receive 
in this study is 1.1 rem, which is below the 5.0 rem per year NIH Radiation Safety Committee guideline for adults. The 
average person in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such as the 
sun, outer space, and the earth's air and soil.  If you would like more information about radiation, please ask the 
investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects. 
While there is no direct evidence that the amount of exposure received from participating in this study is harmful, there is 
indirect evidence it may not be completely safe.  There may be a very slight increase in the risk of cancer.  
Please tell your doctor if you have had any radiation exposure in the past year, either from other research studies or from 
medical tests or care, so we can make sure that you will not receive too much radiation. Radiation exposure includes x-
rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in which 
radioactive materials were injected into your body.  
If you are pregnant you will not be permitted to participate in this research study. 
Genetic Testing 
If a genetic cause of hypoparathyroidism is suspected, you may be offered the option of genetic testing.  Genetic testing 
will be done though another certified laboratory.  You will be asked to sign a different consent form.  The laboratory 
consent form lists additional testing procedures that are not part of this study and will not be done.  We will discuss with 
you which tests will and will not be done for this research study. You can receive a copy of the genetic testing report if 
you wish You do not have to have genetic testing to be in this study.   
Genetic testing can provide information about how health or illness is passed on within your family. This knowledge may 
affect your emotional wellbeing. You might feel differently about your life if you learned that you or your children were at 
increased risk of a disease, especially if there were no treatments. Your children, brothers or sisters may find out that 
they are at risk for health problems because of information found out about you, which might affect your relationships 
with them.  Other family members may also be affected by uncovering risks they have but did not want to know about. 
This information can cause stress, anxiety, or depression.   


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 8 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Your genetic information will be kept confidential to the extent possible. The results of your genetic testing will be kept in 
a locked and secured manner at the NIH.   Genetic information about you will not be revealed to others, including your 
relatives, without your written permission. Problems, such as with insurance or employment discrimination, may occur if 
you disclose information about yourself or agree to have your research records released.  We will not release any 
information about you or your family to any physician, insurance company or employer unless you sign a document 
allowing release of the information. 
Use of Stored Samples 
Your blood, urine and bone samples will be stored in secured freezers on the NIH campus. Your name and identifying 
information will not be on the samples; we will assign them a code. The key to the code will be kept in a separate, secure 
area.  
 
Your sample may be used for other research projects, including those not related to hypoparathyroidism if you agree. 
The samples may be shared with researchers at NIH and outside of NIH.   Please initial on the line below that reflects 
your choice: 
______My samples may be used for other research projects including those not related to hypoparathyroidism.   
______ I do not want my samples used for other research projects. Please destroy my samples once this project is 
complete. 
If you withdraw from this research project before it is complete, you may request that any remaining samples you have 
contributed will be discarded. Results obtained before you withdraw will be kept and your privacy will be protected.  
Commercial products may be developed from your and others’ research samples. You or your beneficiaries will not be 
paid if a product, process, or service is developed from the use of your samples. 
 
Anticipated Benefits 
Treatment with PTH will replace the hormone you are missing. Your disease may be better controlled on PTH than on 
calcium and calcitriol. 
Right of Withdrawal and Conditions for Early Withdrawal 
You may decide to withdraw from the study at any time. The study doctor can withdraw you from the study at any time.  
You will be withdrawn if it is not in your best interest to continue.  Or you will be withdrawn if you cannot comply with 
study requirements. If you become pregnant, if you do not respond well to PTH, or if you develop certain conditions, the 
study doctor will have to withdraw you from the study. The study doctor can tell you about those conditions.   If you are 
planning to become pregnant within 5 years of starting the study, then you should not participate in this study. 
If you or the study doctor elects to discontinue study medication, you may be asked to return to the NIH for tests or 
exams. You have the right to refuse these tests and exams. 
Results from This Study 
You will be informed of any new findings that develop during this study that might relate to your willingness to continue 
to participate. You will be informed of any new information about hypoparathyroidism that might affect your health. 
Study Termination 
If the study is stopped early, you will not continue to receive PTH from the NIH.  The study may be stopped early for 
several reasons, including subject safety.   
 


 
 
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-D-0016 
CONTINUATION: Page 9 of 10 pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Alternatives to Participation or Treatment 
You do not have to be in this study to get treatment for hypoparathyroidism. The standard treatment is oral calcium and 
calcitriol. You may receive the standard treatment from doctors who treat patients with hypoparathyroidism. You might 
be able to persuade your personal doctor to prescribe PTH.  Also, you may be eligible for participation in other clinical 
trials that are evaluating treatments. 
Compensation and Travel Costs 
You will not be paid to participate in this study.  Travel/subsistence expenses and research-related co-pays will be 
reimbursed.  This is based on to the NIH policy established January 5, 2009. 
Posting of Research Results on www.ClinicalTrials.gov 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the results. You 
can search this Web site at any time. 
 
 


 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•Adult Patient or    •Parent, for Minor Patient 
 
STUDY NUMBER: 
07-D-0016 
 
 
CONTINUATION:  Page 10 of 10 pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health.  Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator, Rachel I. Gafni, MD, Building 
30, Room 228, Telephone: 301-594-9924. You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
 
 
 
 
 
 
 
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. 
Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
 
 
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM MARCH 25, 2015 THROUGH MARCH 24, 2016. 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name