Exhibit 10.13

 

Confidential Treatment Requested

Under 17 C.F.R. §§ 200.80(b)(4) and 240.24b-2

 

Work Statement NB-3

 

WORK STATEMENT

 

This Work Statement NB-3 is entered into as of February 21, 2013 pursuant to
Section 2.1 of the Clinical Trial Services Agreement dated as of March 29, 2011,
by and between Radius Health, Inc. (“Radius”) and Nordic Bioscience Clinical
Development VII A/S (“NB”) (the “Agreement”).  Capitalized terms used in this
Work Statement NB-3 and not defined in this Work Statement NB-3 are used with
the meanings ascribed to them in the Agreement.  This Work Statement NB-3 is
attached to and becomes, upon execution by both parties below, a part of the
Agreement, and sets forth the specific terms and conditions relating to the
Services and Deliverables described herein.

 

In consideration of the mutual promises contained in the Agreement and for other
good and valuable consideration the receipt and adequacy of which each of the
parties does hereby acknowledge, the parties hereby agree to the terms of this
Work Statement NB-3 entitled: BA058-05-005 “An Extension of Study BA058-05-003
to Evaluate 18 Months of BA058 Injection 80 µg/Placebo Treatment Followed by Six
Months of Standard-of-Care Osteoporosis Treatment.”

 

This Work Statement NB-3 contains the following Attachments, each of which is
made a part hereof:

 

Attachment A – Specifications/Key Assumptions/Services/Division of
Responsibilities/Timeline Specifications

Attachment B – Budgets, Fees, Pass-through Costs, and Payment Schedule

Attachment C – Materials Provided by Either Party

Attachment D – Core Team Members/Key Personnel

Attachment E – Protocol or Protocol Summary

Attachment F – Reports and Information Management/Regular Meetings

Attachment G – Special Insurance

Attachment H - Transfer of Obligation

Attachment I – Clinical Trial Agreement Template

Attachment K - Indemnity Letter Template

 

IN WITNESS WHEREOF the parties have executed this Work Statement NB-3 intending
it to take effect as an instrument under seal as part of the Agreement as of
February 21, 2013.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

 

By:

/s/ B. Nicholas Harvey

 

By:

/s/ Bente Juel Riis

 

 

 

 

 

Name:

B. Nicholas Harvey

 

Name:

Bente Juel Riis

 

 

 

 

 

Title:

Chief Financial Officer

 

Title:

Chief Executive Officer

 

 

 

 

 

Date:

February 21, 2013

 

Date:

February 21, 2013

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

1

--------------------------------------------------------------------------------

 

Work Statement NB-3

 

Attachment A

 

Specifications/Key Assumptions/Services/Division of Responsibilities/Timeline
Specifications

Study Assumptions

 

Radius Health, Inc.

Protocol:  BA058-05-005, “An Extension of Study BA058-05-003 to Evaluate 18
Months of BA058 Injection 80 µg/Placebo Treatment Followed by Six Months of
Standard-of-Care Osteoporosis Treatment”

 

Protocol Number: BA058-05-005

 

 

Number of Sites:

 

29

Argentina

 

1

Brazil

 

5

Czech Republic

 

3

Denmark

 

3

Estonia

 

2

Hong Kong

 

1

India

 

0

Lithuania

 

1

Poland

 

6

Romania

 

1

USA

 

6

Visits per Completed Subject:

 

3

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Clinical Trial Timeline and Budget

 

RADIUS

BA058-05-005

Protocol 23 July 2012

Cost Proposal 06 February 2013

 

Sponsor:

 

RADIUS

 

 

Protocol ID:

 

BA058-05-005

 

 

Development Phase:

 

III

 

 

Disease:

 

Osteoporosis

 

 

Total # of Randomized and completed subjects

 

925

 

 

Nordic Start Study Activity

 

1-Apr-12

 

 

Expected Date of FPFV:

 

1-Oct-12

 

 

Expected Length of Recruitment (months):

 

18

 

 

Treatment duration (months)

 

6

 

 

Follow-up duration (months)

 

0

 

 

Close Out (months)

 

3

 

 

Duration of Nordic Involvement

 

27

 

 

Number of visits per patient:

 

3

 

 

Number of Countries:

 

10

 

Ar, Br, Dk, Cz, Ee, Li, Po, Ro, HK, USA

Number of Sites:

 

29

 

Ar x 1, Br x 5, Dk x 3, Cz x 3, Ee x 2, Li x 1, Po x 6, Ro x 1, HK x 1, USA x 6

 

Total Budget

 

EURO

 

 

 

 

Clinic Fee

 

[*]

 

925 subjects

 

 

Standard of Care Fee

 

[*]

 

 

 

 

CRO Activities (Nordic Bioscience)

 

[*]

 

All sites; excluding India

 

 

Central Lab Fee (Synarc Lab)

 

[*]

 

Shipment not included. Will be invoiced as pass through. Estimated to be 250,000
Euro

 

 

EDC system

 

 

 

Pass through. Estimated to be below 100,000 Euro

 

 

Calcium and D

 

 

 

Pass through. Estimated to be 15 Euro per month per subject

 

 

Alendronate

 

 

 

Pass through. Estimated to be 30 Euro per month per subject

 

 

Total Budget (Euro)

 

4,519,863

 

6,101,815

 

1.350

 

 

 

USD

 

USD

Central Imaging Reading (Synarc Imaging)

 

579,495

 

Scalable and invoiced as pass through + shipment estimated 19,782 USD

Total Budget (USD)

 

6,681,310

 

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

1

--------------------------------------------------------------------------------

 

Pass through Cost

 

EURO

 

Containers for 24-h urine collection

 

Included

 

Local Hematology Test’s

 

Included

 

Advertisement

 

Included

 

Monitoring Travel Expenses & Accomodations/ other travels

 

Included

 

Translation

 

Included

 

Investigator Meeting

 

Included

 

Alendronate

 

Not included

 

Image and Lab shipments

 

Not included

 

Submission Fee to ERC and CA

 

Not included

 

EDC system

 

Not included

 

Data Monitoring Committe

 

Not included

 

Patient insurrance

 

Not included

 

Annual reports to the FDA

 

Not included

 

External advisory Board

 

Not included

 

Statistical Data analysis and Clinical Study Report

 

Not included

 

 

Payment schedule

 

Euro

 

 

 

 

 

 

 

 

 

Upfront

 

[*]

 

17.84275262

%

1,641 per enrolled subject

 

[*]

 

33.58342833

%

216,784 per month for 7 months

 

[*]

 

33.57375989

%

Subtotal

 

3,841,881

 

84.99994084

%

Rest

 

677,982

 

15.00005916

%

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

2

--------------------------------------------------------------------------------

 

Work Statement NB-3

 

Attachment B

 

Budgets, Fees, Pass-through Costs, and Payment Schedule*

BA058-05-005 Protocol 23 July 2012

 

The Cash budget is Euro 4,519,863 and USD 579,495

 

The Bonus Equity Payment Amount budget is Euro 4,519,863 and USD 310,000

 

The Cash budget will be paid as follows:

 

·                  18% (Euro 806,468) has been paid at signing of the LOI dated
October 22, 2012.

·                  [*]% (Euro [*]) of the Euro cash budget will be paid during
enrollment at Euro [*] per randomized patients at all non-US sites (the SITES).

·                  The USD budget will be paid according to invoices received
from Synarc Inc.

·                  [*]% (Euro [*]) of the Euro cash budget will be paid on a
monthly basis over [*] months starting after patient randomization is completed
with Euro [*] per month.

·                  The USD budget will be paid according to invoices received
from Synarc Inc.

·                  [*]% (Euro [*]) of the Euro cash budget will be paid when the
database is locked and transferred to and accepted by Radius.

·                  The USD budget will be paid according to invoices received
from Synarc Inc.

 

Pass through costs will be invoiced on a monthly basis.

 

The Equity budget will be paid in concert with the cash payment after the same
model as for Work Statement NB-1 and NB-2 under an amended Stock Issuance
Agreement modeled on the Amended and Restated Stock Issuance Agreement entered
into by the parties as of May 16, 2011.

 

The pricing specified in this Budget is calculated based upon 925 subjects
randomized and completed but will be adjusted for the number of completed
patients greater or less than 925 subjects as follows (i) on a fully pro rata
basis for the Clinic Fee, the Central Lab Fee and the Central Imaging Reading
Fee; and (ii) by an amount of euro [*] per subject for the CRO Activities Fee.
However, the Cash Budget and the Bonus Equity Payment Amount shall be reduced by
an amount of euro [*] per subject for Clinic Activities not performed at the
SITES for any patients enrolled in the United States. Such reduction to be
applied in pro rata installments to monthly payments after patient randomization
is completed.  Otherwise, all pricing will be adjusted on a pro rata fashion to
reflect the actual study activities completed by the study subjects.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

 

Attachment C

 

Materials Provided by Either Party

 

Trial Activities & Delegation of Responsibilities

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Sponsor & Service provider Governance

 

 

 

 

 

 

CCBR - Radius Governance Committee

 

ü

 

ü

 

Sponsor and Service provider will be responsible for creating an Executive
Governance Committee to oversee program strategy and implementation.

Clinical Trial Joint Development Team

 

ü

 

ü

 

Sponsor and Service provider will appoint members of the clinical trial joint
development team to implement the clinical study.

 

 

 

 

 

 

 

Regulatory

 

 

 

 

 

 

IND/CTA Preparation

 

R

 

ü

 

Sponsor will be responsible to create all IND and CTA submission documents.
Service provider will be responsible for any required translations for the CTA.

FDA IND Submission & Updates

 

 

 

ü

 

Sponsor will be responsible for all FDA submissions.

CTA Submissions & Updates

 

ü

 

A

 

Service provider will be responsible for all CTA submissions. Sponsor approval
of the submissions is required prior to submission. Sponsor is responsible for
USA.

Health Authority, EC, IRB Queries & Response

 

ü(ex-US)

 

ü(US)

 

Sponsor and Service provider will be responsible to provide responses to Health
Authority, Ethics Committee, and IRB queries, if necessary.

EUDRACT Registration

 

ü

 

ü

 

Sponsor will be responsible to register the clinical study to obtain an EUDRACT
number and service provider will create the XML file for submission.

Investigator’s Brochure

 

 

 

ü

 

Sponsor will be responsible to create the Investigator Brochure and any updates.

Clinical Study Protocol

 

R

 

ü

 

Sponsor will be responsible to create the study protocol, and any amendments, if
necessary. Service provider will be responsible to review the study protocol and
any amendments, if necessary.

Clinical Study Extension Protocol

 

R

 

ü

 

Sponsor will be responsible to create the Extension study protocol, and any
amendments, if necessary. Service provider will be responsible to review the
Extension study protocol and any amendments, if necessary.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Informed Consent Form (ICF, PIS)

 

R

 

ü

 

Sponsor will be responsible to create the Informed Consent Documents and/or
Patient Information Sheets. Service provider will be responsible to review the
ICF or PIS.

Ethics (IRB) Committees submissions & Updates

 

ü(ex-US)

 

ü(US)

 

Service Provider will be responsible for country and site Ethics Committees
(IRB)

FDA SAE Submission & Follow Up(s)

 

 

 

ü

 

Sponsor will be responsible for SAE submissions to USA. See Health Authority
reporting in Safety and Pharmacovigilance

Health Authority SAE Submissions & Follow Up(s)

 

ü

 

A

 

Service provider will be responsible for all Health Authority SAE submissions
except USA. Sponsor will be responsible for approving the HA submissions. See
Health Authority reporting in Safety and Pharmacovigilance

Legal representative (if required)

 

ü

 

 

 

Service provider will be responsible to provide Legal Representative services,
on behalf of the sponsor, if required by local regulation.

Regulatory & Study Documents translations

 

ü

 

ü

 

Service provider will be responsible to provide all necessary document
translations for regulatory and study documents.

Clinicaltrials.gov registration & management

 

 

 

ü

 

Sponsor will be responsible to register the clinical study on clinicaltrials.gov
and manage the status of the study as required by regulation.

Clinical Trial Materials

 

 

 

 

 

 

Calcium and Vitamin D

 

ü

 

 

 

Service provider will manage sites to purchase calcium and vitamin D.

Alendronate

 

ü

 

ü

 

Service provider will manage sites to purchase initial supply of Alendronate
until such time as Sponsor can provide Alendronate from a central source. Where
central supply is not feasible, service provider will continue to manage local
alendronate purchase.

Qualified Person for Drug Release

 

 

 

ü

 

Sponsor will be responsible for shipping study drug to the study centers

Study Drug Shipping

 

 

 

ü

 

Sponsor will be responsible for shipping study drug to the study centers.

Package Clinical Trial Materials

 

NA

 

ü

 

Sponsor will be responsible to package the clinical trial material, including
payment of any third party costs related to packaging.

Country specific labels

 

NA

 

ü

 

Sponsor will be required for labeling

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

 

 

 

 

 

 

the study drug kits. Service provider will be responsible to provide label
translation and review label prior to packaging.

Instructions for Use - Alendronate

 

NA

 

NA

 

Sponsor is responsible to provide the Package inserts

Sharps containers

 

NA

 

NA

 

 

Alcohol Swabs

 

NA

 

NA

 

 

Study Drug Release & Distribution (IVRS)

 

NA

 

NA

 

 

Study Drug Reconciliation — Patient, Site, & Study

 

ü

 

R

 

Service provider will be responsible to perform site level drug accountability
during the clinical study. Each alendronate and vitamin D and calcium tablet
will need to be accounted for during and at the end of the study for each
patient at every clinical site.

Study Drug Destruction

 

 

 

ü

 

Sponsor will be responsible for final study drug destruction and accountability.

Study Drug: Import Broker, License & Requirements

 

 

 

ü

 

Sponsor will be responsible to provide all information necessary to import the
study drug and clinical trial materials, as needed. Sponsor will be responsible
to contract with a local customs or import broker to facilitate the import of
clinical trial materials, if necessary.

Proforma Invoice

 

 

 

ü

 

Sponsor will be responsible to create the proforma invoices for importing study
drug. Sponsor will be responsible to provide necessary information to complete
the proforma invoice.

Clinical Trial Conduct

 

 

 

 

 

 

Data Safety Monitoring Board

 

 

 

ü

 

Sponsor will be responsible to create a Data Safety Monitoring Board for the
clinical study as needed.

Clinical Trial Project Plan

 

R

 

ü

 

Sponsor will be responsible for developing a Clinical Trial Project Plan to
identify the goals, objectives, timelines, milestones, organization chart,
vendor list (including roles & responsibilities), and budget forecast and
tracking for the clinical study. The Sponsor will be required to approve the
clinical trial project plan prior to screening.

Clinical Trial Budget Forecasting & Tracking

 

ü

 

R

 

Service provider will be responsible for forecasting and tracking the trial
expense and reporting to the Sponsor on a monthly basis.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Clinical Trial Insurance

 

 

 

ü

 

Sponsor will be responsible for obtaining and maintaining insurance for the
clinical trial. Sponsor will be responsible to provide proof of insurance to the
Service provider, as required.

Safety Monitoring

 

ü

 

 

 

Service provider will be responsible for safety monitoring.

Medical Monitoring

 

 

 

ü

 

Sponsor is responsible for Medical Monitoring

Vendor Management - Labs, Dexa, EDC

 

ü

 

 

 

Service provider will be responsible for qualifying, contracting, payment for
services, data collection, and quality and compliance for any service contracted
out by the Service provider.

Vendor Management — Central Drug Manufacture/Package

 

 

 

ü

 

For geographies where central supply is feasible, Sponsor will secure
centrally-sourced alendronate and ensure appropriate packaging for clinical use
as needed.

Vendor Management - PK, AntibodyIVRS

 

NA

 

NA

 

 

Vendor Payments

 

ü

 

ü

 

Sponsor and Service provider will be responsible to pay third party vendors to
whom they have contracted required study services.

Patient Recruitment, Screening, Enrollment

 

ü

 

R

 

Service provider will be responsible for patient recruitment, screening, and
enrollment. Service provider will provide, until enrollment completes, the
Sponsor with a weekly update of cumulative number of patients completed for 003
by week, , number screened within the reporting week, number screened but not
enrolled, number failed screening, and number enrolled in 005.

Site Selection

 

N/A)

 

N/A

 

Site selection pre-determined in 003 study.

Site Management

 

ü

 

 

 

Service provider will be responsible for site management activities.

Site Confidentiality Agreements

 

ü (ex-US)

 

ü (US)

 

Service Provider will be responsible to collect Site Confidentiality agreements
prior to communicating any study specific information. A copy of the CDA will be
sent to the Sponsor upon execution of the document..

Site Contract/Agreement

 

ü (ex-US)

 

ü (US)

 

Service Provider will be responsible to create and manage the Site Contracts. A
copy of the Site Agreement will be sent to the Sponsor upon execution of the
document.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Clinical Trial Monitoring & Plan

 

ü

 

A

 

Service provider will be responsible to create a clinical trial monitoring plan
as per the Service provider’s SOP for Clinical Monitoring and monitor the
clinical study conduct at the sites. The Sponsor is responsible for approving
the monitoring plan prior to study start.

Clinical Trial Monitoring Reports

 

ü

 

R

 

Service provider will be responsible to create clinical trial monitoring reports
that document the clinical trial monitoring visit. The clinical trial monitoring
report will be generated using the format identified in the Service provider’s
SOP. The monitoring reports will be made available to the Sponsor for review
within 10-20 days of the monitoring visit - .

Clinical Trial Monitors

 

ü

 

A

 

Service provider will be responsible to provide qualified clinical trial
monitors to perform required monitoring duties.

Monitor Travel Expense

 

ü

 

 

 

Service provider will be responsible for monitoring expenses.

 

 

 

 

 

 

 

Sponsor Meetings

 

ü

 

ü

 

Sponsor and Service provider will be responsible for scheduling Sponsor Meetings
on a weekly basis during enrollment and monthly after enrollment completes.
Meetings can also happen on an ad-hoc basis as required by the Sponsor or
Service provider.

Sponsor Meeting Minutes

 

A

 

ü

 

Sponsor will be responsible to create the meeting minutes for the Sponsor
meetings and circulate a draft within 24 hours. Service provider will review and
provide comment within 24 hours. Meeting minutes will be required to be final
within 72 hours.

Trial Staff Training

 

ü

 

R

 

Service provider will be responsible for training of all trial staff as well as
documenting the training for new trial staff members and retraining of existing
trial staff members. The training records will be made available for the
Sponsor’s review.

Investigator Meeting & Training

 

ü

 

ü

 

Service provider will be responsible for planning and conducting the study
investigator meetings. Sponsor will be responsible to assist in the preparation
and approval of

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

 

 

 

 

 

 

investigator meeting training materials.

Central Imaging Analysis (BMD)

 

ü

 

 

 

Service provider will be responsible to provide central imaging services to
assess the protocol required measures for bone mineral density.

Protocol Deviation & Waiver

 

ü

 

ü

 

Service provider will be responsible to identify and/or collect all protocol
deviations and violations. All violations will be reviewed by the Study Safety
Officer and the Medical Monitor prior to deciding if the patient can participate
sin the study or must be excluded. Waivers should minimized and
inclusion/exclusion criteria adhered to.

Sponsor Project Update Reports

 

ü

 

 

 

Service provider will be responsible to create monthly study status update
reports as agreed with the CTL and MD.

Trial Master File

 

ü

 

 

 

Service provider will be responsible to create, maintain, and reconcile the
trial master file including all required Essential Documents. At the end of the
study, the trial master file will be sent to the Sponsor. The Sponsor will be
responsible for archiving the trial master file. The TMF is electronic.

Site Trial File

 

ü

 

 

 

Service provider will be responsible to ensure the site trial file is complete
at all times during the study. The Service provider will be responsible to
reconcile the site file against the trial master file site file.

Investigator Site Payments

 

ü (ex-US)

 

ü (US)

 

Service provider will be responsible for site payments except the US.

Essential Document Collection

 

ü

 

 

 

Service provider will be responsible to collect and file all required GCP
Essential Documents. The Essential Documents will be part of the trial master
file.

Printing Study Documents

 

ü

 

 

 

Service provider will be responsible to print or contract printing services for
all study documents for sites and patients.

Labs

 

 

 

 

 

 

Central or Local Safety Labs

 

ü

 

 

 

Service provider will be responsible for the central and safety lab vendor
contracting, management, payments, sampling of patient samples, and reporting of
sample results.

Central/Safety/Bone Marker Labs Data Reporting (SI Units)

 

ü

 

 

 

Service provider will be responsible for the transfer specification and

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

 

 

 

 

 

 

transfer of lab data from the central labs. Service provider will be responsible
for validating the transfer and reconciling the lab data with the study
database.

Abnormal lab value flags

 

ü

 

 

 

Service provider will be responsible for creating flags for abnormal lab values
and ensuring these are communicated to the clinical sites.

Lab Specimen Management, Shipping & Reconciliation

 

ü

 

 

 

Service provider will be responsible for lab sample management, shipping and
storage according to the required conditions, and reconciliation.

Lab Manual

 

ü

 

A

 

Service provider will be responsible to develop a lab manual with lab
collection, handling, and shipping instructions for distribution to the site.
The Sponsor will be responsible to approve the lab manual prior to study start.

Lab Kits & Supplies

 

ü

 

 

 

Service provider will be responsible to provide the lab kits and supplies to the
study sites.

Lab Sample Storage

 

ü

 

 

 

Service provider will be responsible for storage of lab samples according to the
required conditions until all lab data are final and reported.

Lab Sample Destruction

 

ü

 

A

 

Service provider will be responsible for destroying lab samples. Sponsor
approval is required prior to destroying any lab samples.

Bone Marker Analysis & Data Reporting

 

ü

 

 

 

Service provider is responsible for the bone marker sample analysis and data
reporting. The data transfer will be validated and reconciled with the study
database.

PK & PK Data Reporting

 

NA

 

NA

 

 

Antibody (including NAbs) analysis & Data Reporting

 

 

 

ü

 

Sponsor will be responsible for Anti-drug antibody and neutralizing antibody
sampling and data reporting.

Data Management

 

 

 

 

 

 

Data management plan

 

ü

 

A

 

Service provider will be responsible to create the Data Management Plan for the
study upon approval of the CRF. Sponsor will be required to approve the plan
before first patient first visit..

Annotated Case Report Form

 

ü

 

A

 

Service provider will be responsible to create the Annotated Case Report Forms
based on CDISC SDTM. .

CRF

 

ü

 

A

 

Service provider will be responsible to create the Case Report Forms for data
entry. Sponsor will be required to approve the CRF during the eCRF

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner

A = Approve

R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

 

 

 

 

 

 

user acceptance tests (eCRF screen review meetings).

CRF Completion Instructions

 

ü

 

 

 

Service provider will be responsible to create the CRF completion instructions
and distribute to the study sites. Sponsor will be required to approve the CRF
completion instructions prior to site distribution.

Data validation checks

 

ü

 

R

 

Service provider will be responsible to create the data entry data validation
checks. The data validation checks will be provided for Sponsor review.

Database Development, Testing, and Validation

 

R

 

ü

 

Service provider will be responsible for database development, testing, and
validation in compliance with 21 CFR Part 11.

EDC System User Acceptance Testing

 

ü

 

 

 

Service provider will be responsible for user acceptance testing the EDC system
before it is release for production environment. Changes to the EDC system
during the study must be tested before released to production

Data Cleaning & Query Management

 

ü

 

R

 

Service provider will be responsible to manage the study data collection, data
cleaning, and query management process.

Double Data Entry

 

NA

 

 

 

For paper-based CRFs, Service provider will be responsible to double data enter
the CRF data into the study database.

Data Transfers Specifications

 

ü

 

R

 

Service provider will be responsible to create the data transfer specifications
for all data collected outside the study database from third party vendors. The
data transfer specification will be provided for Sponsor review.

Data Transfers & Merge

 

ü

 

ü

 

Service provider will be responsible to collect and validate the external data
transfer and merge the datasets into the study database. The data transfer
specification will be provided for Sponsor review.

DSMB Data Preparation & Transfer

 

ü

 

 

 

Service provider will be responsible for cleaning the data, managing the queries
and preparing a database transfer to the Sponsor’s statistician for a DSMB
meeting.

Data Listings for Medical & Sponsor Review

 

ü

 

R

 

Service provider will be responsible to generate data listings for Medical and
Sponsor Review during the study. The data listings will include: Reasons for
Enrollment Failure, Baseline Demographics (during screening), Adverse Events
(monthly),

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

 

 

 

 

 

 

Concomitant Medications (on request), Study Drug Administration (on request),
Abnormal Labs (monthly), Elevated Calcium (on request).

Data Coding (MeDRA, WHO Drug)

 

ü

 

A

 

Service provider will be responsible to code all Adverse Events, Medical History
and Concomitant Medications with MeDRA and WHO Drug and provide medical review
and oversight of the coding. Sponsor will be responsible to approve the coding
of events and medications appropriately.

eCRF and Query Tracking

 

ü

 

 

 

Service provider will be responsible to manage and track site compliance with
data entry by tracking CRFs and queries.

SAE Database Reconciliation

 

ü

 

A

 

Sponsor and Service provider will be responsible to perform a reconciliation of
the events in the safety and trial database. Service provider will perform an
SAE reconciliation of the trial database with safety & pharmacovigilance
reporting database prior to database lock. The Sponsor will be responsible to
approve the SAE reconciliation has been performed accurately.

Local Tolerance Diary

 

A

 

ü

 

The Sponsor will be responsible to create the Local Tolerance Diary.

Drug Compliance Diary

 

A

 

ü

 

The Sponsor will be responsible to create the Drug Compliance Diary.

Patient CRFs for CSR (SAE or AE Discontinued)

 

ü

 

 

 

Service provider will be responsible to generate copies of the entire individual
patient case report forms for all patients who had a serious adverse event or
discontinued due to adverse event.

Investigator Signoff of Patient eCRF

 

ü

 

 

 

Service provider will be responsible to insure that the investigator has signed
off on the patient case report forms that the data are reviewed and accurate.

Blinded Data Review Meeting with Sponsor

 

ü

 

A

 

Service provider will be responsible to provide the Sponsor with a completed
database for blinded data review prior to database lock. Sponsor will be
required to review and approve the database and data prior to database lock.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Database Lock

 

ü

 

A

 

Service provider will be responsible to lock the study database. Sponsor will be
required to review and approve all changes or queries generated during the
blinded study review meeting have been resolved and the database can be locked.

Data Transfer to Sponsor

 

ü

 

 

 

Service provider will be responsible to transfer the study data and database to
the sponsor.

Data Archiving & PDF

 

ü

 

 

 

Service provider will be responsible to generate data and PDF for archiving.
Service provider will be responsible to provide each study center a data archive
for the sites’ patients.

Safety & Pharmacovigilance

 

 

 

 

 

 

Study Safety Officer

 

ü

 

A

 

Service provider will be responsible to provide a Safety Officer to oversee and
report on any serious adverse event.

Pharmacovigilance (PV) Plan

 

ü

 

A

 

Service provider will be responsible to develop a PV plan that documents the
safety reporting process and health authority submission responsibilities.

Safety Reporting Database

 

ü

 

ü

 

Service provider will be responsible to enter serious adverse events data in a
validated 21 CFR Part 11 compliant database provided by Sponsor.

SAE Site Reporting Form

 

ü

 

A

 

Service provider will be responsible to provide an SAE reporting form at the
start of the study. This form will capture all the necessary reporting
information requiring for submitting a CIOMS form to the Health Authorities.
Sponsor will be responsible to approve the SAE reporting form.

ICSR CIOMS Initial & Follow up Forms

 

ü

 

A

 

Service provider will be responsible to complete the CIOMS form for all initial
and follow up Suspected Unexpected Serious Adverse Event

ICSR Tracking of Health Authority filings

 

ü

 

R

 

Service provider will be responsible to create a tracking tool for all reported
serious adverse events and report status (i.e., initial, follow up, dates of
submission). Study Safety Officer is responsible for performing routine review
of AEs and SAEs and performing an analysis of similar events.

Serious Adverse Event Narrative

 

 

 

ü

 

Sponsor will be responsible to create the SAE narrative for the clinical study
report.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

DSUR; Annual & Periodic Safety Update Generation & Filing

 

ü

 

ü

 

Sponsor is responsible for creating the DSUR and will submit it in USA. Service
provider will be responsible to submit it to all other Health Authorities.

Health Authority Reporting

 

ü

 

ü

 

Sponsor will be responsible to submit SAE CIOMS Initial and Follow up to USA.
Service provider will be responsible to submit the CIOMS Initial and Follow up
to all other Health Authorities. Reports are required to be made within
timelines given in the PV Plan.

SAE CIOMS Site Distribution

 

ü

 

 

 

Service provider will be responsible to notify the sites and distribute the
CIOMS forms to the sites for reporting to local ethics, as required.

SAE Reconciliation with Data Management

 

ü

 

ü

 

Sponsor and Service provider will be responsible to perform an SAE
reconciliation of the trial database with safety & pharmacovigilance reporting
database prior to database lock. The Sponsor will be responsible to approve the
SAE reconciliation has been performed accurately.

Final Safety Report for HA, EC, IRB submission

 

ü

 

ü

 

Sponsor and Service provider will be responsible to create the final safety
report at the end of the study as part of the CSR. Sponsor will submit final
safety report to USA and Service Provider to other HAs and ECs.

Statistics

 

 

 

 

 

 

Randomization Scheme

 

 

 

ü

 

Sponsor’s statistician will be responsible to create and maintain the
randomization scheme only unblinding after database lock.

Statistical Analysis Plan

 

 

 

ü

 

Sponsor’s statistician will be responsible to create the Statistical Analysis
Plan (SAP) prior to database lock.

Statistical Programming

 

 

 

ü

 

Sponsor’s statistician and statistical programmer will be responsible to develop
the statistical programming for the analyses and TLFs

TLF Generation

 

 

 

ü

 

Sponsor’s statistician will be responsible to generate all tables, listings, and
figures for the study.

Data Analysis

 

 

 

ü

 

Sponsor’s statistician will be responsible to perform the study analyses.

DSMB Table Generation

 

 

 

ü

 

Sponsor’s statistician will be responsible to generate the required tables and
data for the DSMB.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

ü = Owner
A = Approve
R = Review

 

 

 

Activity Responsible

 

 

 

 

Nordic
Bioscience

 

Radius
(Sponsor)

 

Expectation

Population PK Analysis Plan

 

 

 

ü

 

Sponsor’s statistician will be responsible to create the PopPK analysis plan
prior to database lock.

Population PK Analysis

 

 

 

ü

 

Sponsor’s statistician will be responsible to generate the programming and
analyses for the Population PK analysis.

Medical Writing

 

 

 

 

 

 

Clinical Study Report

 

 

 

ü

 

Sponsor’s Medical Writer will be responsible to write the clinical study report

CSR Narratives (SAE, AE Discontinuation)

 

ü

 

ü

 

Service provider’s Safety & Pharmacovigilance group will be responsible for
generation the CIOMS forms during the clinical study. The Sponsor’s Medical
Writer will be responsible for generating and incorporating the narratives into
the CSR.

Quality

 

 

 

 

 

 

CRO Qualification

 

 

 

ü

 

Sponsor will be responsible for qualification of the Service provider.

CRO GCP and systems audits

 

 

 

ü

 

Sponsor may be responsible, from time to time, to conduct Service provider GCP
and systems audits.

Third party qualification and audit

 

 

 

ü

 

Sponsor may be responsible, from time to time, to conduct qualifications and
audits for third party vendors.

Investigator site audits

 

 

 

ü

 

Sponsor may be responsible, from time to time, to conduct investigator site
audits.

Health Authority inspections/audits

 

ü

 

ü

 

In the event of an Health Authority inspection of the Service provider or sites,
the Service provider and Sponsor will be responsible for assisting with the
inspection, providing responses to inspector requests, and drafting follow up
responses to the inspection inquiries.

Clinical trial documents review and audit

 

 

 

ü

 

Sponsor may be responsible, from time to time, to review and/or audit the
Service provider’s clinical trial documents (i.e., trial master files).

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

 

Attachment D

 

Core Team Members/Key Personnel

 

The following core team members will conduct the services listed in Attachment
A.

 

Sponsor will be notified of any changes to the core team member.

 

Study Safety Officer

 

Bente Juel Riis

[*]

Clinical Trial Leader

 

Jeppe Ragnar Andersen

[*]

Clinical Trial Manager

 

Morten Thorup Pedersen

[*]

Pharmacovigilance Manager

 

Bodil Simonsen

[*]

Clinical Data Managers

 

Henrik Bo Hansen
Ole Eskildsen

[*]
[*]

Statistical Advisor

 

Inger Byrjalsen

[*]

Medical Coder

 

Lisbeth Heiden

[*]

Head of Central Laboratory

 

Per Qvist

[*]

Clinical Regulatory Coordinator

 

Bodil Simonsen

[*]

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

 

Attachment E

 

Protocol title and date

 

Study Protocol BA058-05-005: An Extension Study to Evaluate Six Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-003, dated 23 July 2012.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Radius Health, Inc.

Confidential

 

[g17732le05i001.gif]

 

CLINICAL STUDY PROTOCOL

 

An Extension Study to Evaluate Six Months of Standard-of-Care Osteoporosis
Management Following Completion of 18 Months of BA058 or Placebo Treatment in
Protocol BA058-05-003

 

This study will be conducted according to the protocol and in compliance with
Good Clinical Practice, the ethical principles stated in the Declaration of
Helsinki, and other applicable regulatory requirements.

 

Protocol Number:

 

Protocol BA058-05-005

Protocol Date (Version):

 

Original (23 July 2012)

EudraCT Number

 

2012-002216-10

IND Number:

 

73,176

Study Sponsor:

 

Radius Health, Inc.
201 Broadway, 6th Floor Cambridge, MA 02139, USA
Tel: 617.551.4700. Fax: 617.551.4701

Sponsor Medical Monitor:

 

Louis Brenner, MD
Chief Medical Officer, Radius Health, Inc.
Tel: 617.551.4006. Fax: 617.551.4701.
Email: [*]

Study Safety Officer

 

Bente Juel Riis, MD
Medical Advisor, Nordic Bioscience A/S
Tel: +45 22 90 13 17. Fax: +41 91 970 2988
Email: [*]

Contract Research
Organization (CRO):

 

Nordic Bioscience A/S
Herlev Hovedgade 207
2730 Herlev, Denmark
Tel: +45 4452 5252. Fax: +45 4452 5251

 

Disclosure Statement
This document contains information that is confidential and proprietary to
Radius Health, Incorporated (RADIUS).  This information is being provided to you
solely for the purpose of evaluation and/or conducting a clinical trial for
RADIUS.  You may disclose the contents of this document only to study personnel
under your supervision and/or to your institutional review board(s) or ethics
committee(s) who need to know the contents for this purpose and who have been
advised on the confidential nature of the document.

 

Protocol BA058-05-005 (Original) 23 July 2012

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

PROTOCOL SYNOPSIS

 

Title:      An Extension Study to Evaluate Six Months of Standard-of-Care
Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo
Treatment in Protocol BA058-05-003

 

Protocol Number:  BA058-05-005

 

Test Drug:  BA058 Injection

 

Study Objectives:

 

The primary objective of this study is to collect clinical information regarding
six months of standard-of-care osteoporosis management, including treatment with
alendronate, in subjects who have previously received 18 months of blinded
treatment with BA058 Injection or Placebo in Study BA058-05-003.  Safety data
will be obtained via clinical, laboratory and radiologic assessments.  Since it
is recommended and anticipated that the majority of the subjects will be treated
with alendronate during the six month study, the study objectives are based upon
alendronate treatment.

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate in
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

Study Population:

 

Subjects with postmenopausal osteoporosis who completed the End-of-Treatment
Visit (Visit 9) for Study BA058-05-003 and were previously randomized to either
blinded BA058 Injection 80 µg or blinded Placebo are eligible for inclusion into
this Extension Study provided that they fulfill the Inclusion/Exclusion criteria
described below.

 

Inclusion/Exclusion Criteria

 

Otherwise healthy ambulatory postmenopausal women who participated in, and who
completed 18 months of treatment with either blinded BA058 Injection 80 µg or
blinded Placebo in Study BA058-05-003, are scheduled to complete or have
completed the End-of-Treatment visit (Visit 9 in Study BA058-05-003), and who
have provided a new written informed consent for the Extension Study, are
eligible for enrollment into this study.  Participants must be no more than 33
days from last dose of study medication in Study BA058-05-003 to be eligible for
this study.  The physical exam and labs from the End-of-Treatment visit from
Protocol BA058-05-003 (Visit 9) of the BA058-05-003 study will provide baseline
data for this Extension Study.  In addition, the subjects must, in the opinion
of the Investigator, be appropriate candidates for further osteoporosis
management.

 

Subjects will not be enrolled if they experienced a treatment-related SAE as
assessed by the Investigator, or if they were withdrawn from Study BA058-05-003
for any reason.  Subjects who are not candidates for alendronate treatment will
receive standard-of-care management determined to be

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

appropriate by the Investigator.  Specific inclusion and exclusion criteria are
described in Section 4.1 and Section 4.2, respectively.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Study Design and Methodology:

 

Number of Subjects

 

All subjects who were randomized to the BA058 Injection 80 µg/Placebo arms in
Study BA058-05-003, and who completed 18 months of treatment will be offered the
opportunity to participate in this study.  There will, therefore, be a potential
maximum of 1,600 subjects eligible to be enrolled in this study.

 

Design

 

This study will be an open-label extension of Study BA058-05-003.  The purpose
of the study is to provide longer term safety data, fracture data and BMD data
after six months of standard-of-care osteoporosis treatment, including treatment
with alendronate, in otherwise healthy ambulatory postmenopausal women with
severe osteoporosis who have previously received 18 months of blinded treatment
with BA058 Injection or Placebo.

 

Subjects randomized to BA058 Injection 80 µg/Placebo in Study BA058-05-003 and
who are candidates for ongoing osteoporosis care, will receive six months of
treatment with oral alendronate at a dose of 10 mg per day.  Subjects who are
sensitive to alendronate, or who are not candidates for alendronate, may also
participate in the study and be treated with an alternative osteoporosis
medication according to the Investigator.  Both groups of subjects will undergo
protocol specified procedures (Section 7.0, Appendix 14.1 and 14.2) including
BMD and fracture assessment.  The study design is presented in Figure 1, below.

 

Figure 1: Protocol BA058-05-005 Study Design

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Figure 1:  Protocol BA058-05-005 Study Design

 

[g17732le07i001.jpg]

 

In this study, the Follow-up Visit from the 18 month study (Visit 10 from Study
BA058-05-003) will serve as the Day 1 Visit (Visit 1) for this six month
extension study (Study BA058-05-005).

 

All subjects will continue to take calcium and vitamin D supplementation
throughout the Extension Study.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Study Visits

 

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility
of participating in the Extension Study will be discussed with subjects
randomized to BA058 80 µg/Placebo.  This Extension Study will be comprised of
standard-of-care osteoporosis management, including six months of treatment with
alendronate, if appropriate.  In the month between Visit 9 and Visit 10 (between
months 18 and 19 of Study BA058-05-003), the Investigator will consider the
results of the assessments performed at Visit 9, including a local review of
BMD, and determine if alendronate, or an alternative therapy, is appropriate for
the subject, as part of this extension study.

 

At the Follow-up (Visit 10 for Protocol BA058-05-003, Day 1 for Protocol
BA058-05-005) subjects; who were randomized to BA058 Injection 80 µg/Placebo,
who fulfill the inclusion/exclusion criteria (Section 4.1 and Section 4.2), and
who have agreed to participate in the Extension Study; will sign the Informed
Consent Form and be enrolled in the study.

 

Alendronate is the recommended osteoporosis treatment for this extension study. 
Subjects who have been determined by the Investigator to be candidates for
alendronate therapy will receive open-label oral alendronate treatment at a dose
of 10 mg per day for six months.  Subjects will be instructed to take their
first dose of alendronate for Study BA058-05-005 in the morning, on the day
following their Day 1 visit.  Subjects who are not candidates for alendronate
will receive alternative standard-of-care management, as determined by the
Investigator, for osteoporosis for six months.

 

All subjects will have clinic visits for study related procedures at Day 1,
Month 3 and Month 6.  For the purpose of this study one month is equal to 30
days.

 

Statistical Considerations:

 

Exploratory statistical analyses will assess longer term safety, fracture
incidence (including vertebral and non-vertebral fracture), and BMD change
following treatment with alendronate for six months after the completion of a
subject’s participation of 18 months in study BA058-05-003.

 

Fractures and BMD Analyses

 

All specified endpoints will be summarized by treatment group and study period
using standard descriptive statistics (n, mean, SD, median, minimum, maximum or
n and %, as appropriate).  The fracture incidence; either clinically or
radiologically determined, based on clinical events or protocol-directed
vertebral x-rays at Month 6 of this Extension Study; will be tabulated.  In
addition, BMD results from the six months of treatment with alendronate will
also be tabulated, with additional tabular categories for results from the
entire contiguous 24 months from baseline of study BA058-05-003 through the end
of Study BA058-05-005, as well as the results during the 18 months of study
BA058-05-003, for subjects who eventually enter study BA058-05-005.  These
descriptive analyses will be conducted on all subjects with baseline and
post-baseline data.  The analyses for the group that does not receive
alendronate will also be descriptive in nature.

 

Safety Analysis

 

Data will be summarized and tabulated based on the enrolled population for this
Extension Protocol.  All subjects enrolled in the Extension Protocol will be
included in the safety analysis that will be performed on the following
parameters:

 

·                  Incidence and severity of AEs.

 

·                  Pathological changes in hematology, chemistry and urinalysis
data based on normal ranges supplied by the clinical laboratory, if applicable.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Safety assessments for changes in physical examination, vital signs, ECG, and
laboratory tests will be descriptively summarized by treatment and study
periods.  Concomitant medication classes will be categorized using World Health
Organization (WHO) drug dictionary and summarized by number and percent of
subjects using each class by treatment group.  All treatment emergent adverse
events (TEAEs) will be coded for system organ class (SOC) and preferred term
(PT) using MedDRA and the number (%) of subjects experiencing each AE (SOC/PT)
will be summarized by treatment, relationship to treatment, and severity.  All
serious adverse events (SAE) will be listed and the number (%) of subjects with
an SAE presented by treatment group.

 

Procedures and Assessments

 

Fractures and BMD

 

The End-of-Treatment (Visit 9) evaluations for vertebral fracture assessment,
non-vertebral fracture assessment and BMD from Study BA058-05-003 will serve as
the baseline evaluations in this study.  The Day 1 assessment will be concurrent
with the Follow-up Visit (Visit 10) for Study BA058-05-003.  Subjects will
return to the clinic for assessment of BMD at spine, hip and wrist (for those
subjects who had wrist DXAs performed in Study BA058-05-003) at Month 6. 
Clinical and radiographic assessments for fractures, bone marker assessments of
anabolism (PINP, bone-specific alkaline phosphatase and osteocalcin) and
resorption (CTX) will be performed at Month 6.

 

Safety

 

Safety evaluations performed will include physical examinations, vital signs,
12-lead ECGs, clinical laboratory tests, and monitoring and recording of adverse
events.

 

Complete details of the study assessments are provided in Section 7.0, in the
Schedule of Visits and Procedures (Appendix 14.1) and in the Suggested Schedule
of Events and Procedures by Study Visit (Appendix 14.2).

 

Treatments Administered

 

Alendronate sodium (Fosamax®, Merck & Co., Inc., or other approved generic
manufacturer) 10 mg tablets for oral administration contain 13.05 mg of
alendronate monosodium salt trihydrate which is the molar equivalent of 10 mg
free acid and excipients.  Alendronate should be stored in a well-closed
container at room temperature, 15-30ºC.  The alendronate may be generic
substitutable approved versions which contain different inactive ingredients,
but the amount of active free alendronate must be equivalent to 10 mg. 
Alendronate will be sourced locally by the medical center and reimbursed by the
Sponsor.

 

Any alternative treatment(s) for osteoporosis will be sourced locally at the
discretion of the Investigator.  The Sponsor and the Investigator will not
provide or be responsible for the costs of the alternative medication, should
one be prescribed.  This will be at the discretion of the Investigator and
subject.

 

Calcium (500—1000 mg) and vitamin D (400—800 IU) supplements will be sourced
locally by the medical center and provided to the subjects at the expense of the
Sponsor.  Independent of alendronate, or other prescribed osteoporosis
medication, subjects will continue to take calcium and vitamin D as they did in
Study BA058-05-003.

 

Duration of Subject Participation:

 

Participation will be approximately seven months (28 weeks) from enrollment to
completion of final study evaluations.  In combination with Study BA058-05-003,
subjects will participate in this clinical

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

postmenopausal osteoporosis program for 26 to 27 months.  The first visit of
Study BA058-05-005 will be concurrent with Visit 10 of Study BA058-05-003.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

TABLE OF CONTENTS

 

PROTOCOL SYNOPSIS

3

 

 

 

Table of Contents

10

 

 

 

List of Abbreviations

14

 

 

 

1.0

introduction

16

 

1.1

Background Information

16

 

1.2

Drug Under Study

16

 

 

1.2.1

Efficacy of Alendronate

16

 

 

1.2.2

Safety of Alendronate Sodium

17

 

1.3

Study Rationale and Selection of Doses

18

 

 

1.3.1

Study Rationale

18

 

 

1.3.2

Study Design

18

 

 

1.3.3

Study Population

19

 

 

1.3.4

Selection of Endpoints

19

 

 

1.3.5

Selection of Dose

19

 

 

 

2.0

STUDY OBJECTIVES

19

 

 

 

3.0

INVESTIGATIONAL PLAN

20

 

3.1

Overall Design and Study Plan

20

 

 

3.1.1

Treatment Period

21

 

 

 

4.0

SELECTION OF STUDY POPULATION

22

 

4.1

Number of Subjects

22

 

4.2

Inclusion Criteria

22

 

4.3

Exclusion Criteria

22

 

4.4

Withdrawal of Subjects from the Study

23

 

4.5

Temporary Suspension of Treatment

23

 

4.6

Replacement of Subjects

23

 

 

 

5.0

STUDY TREATMENTS

24

 

5.1

Study Medications

24

 

 

5.1.1

Alendronate

24

 

 

5.1.1.1

Restrictions on Alendronate Use

24

 

 

5.1.2

Alternative Osteoporosis Medication

24

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

 

 

5.1.3

Calcium and Vitamin D Supplements

24

 

5.2

Packaging, Labeling and Storage

24

 

 

5.2.1

Storage

24

 

5.3

Treatment Assignment

25

 

5.4

Study Medication Administration

25

 

 

5.4.1

Alendronate Administration

25

 

 

5.4.2

Alternative Osteoporosis Medication Administration

25

 

5.5

Treatment Compliance

25

 

5.6

Unblinding of Study Medication

26

 

 

 

6.0

CONCOMITANT MEDICATIONS

26

 

6.1

Concomitant Medications

26

 

6.2

Prohibited Medications

26

 

 

 

7.0

STUDY ASSESSMENTS

27

 

7.1

Clinical Procedures/Assessments

27

 

 

7.1.1

Informed Consent

27

 

 

7.1.2

Medical History

27

 

 

7.1.3

Physical Examination

27

 

 

7.1.4

Vital Signs

27

 

 

7.1.5

Orthostatic Blood Pressure and Heart Rate

27

 

 

7.1.6

Electrocardiogram

28

 

 

7.1.7

Clinical Laboratory Evaluations

28

 

 

7.1.8

Clinical Chemistry and Urinalysis (Dipstick)

28

 

 

7.1.9

Hematology

29

 

 

7.1.10

Coagulation

29

 

 

7.1.11

24-Hour Urine Collection

29

 

 

7.1.12

Bone Mineral Density

30

 

 

7.1.13

Serum Markers of Bone Metabolism

30

 

 

7.1.14

Clinical and Radiologic Evaluation of Fractures

30

 

 

7.1.15

BA058 Antibody Assessments

30

 

 

7.1.16

Subject Diaries

31

 

 

7.1.17

Activity and Diet

31

 

 

 

8.0

ADVERSE EVENTS AND SAFETY EVALUATION

31

 

8.1

Definitions, Documentation, and Reporting

31

 

 

8.1.1

Adverse Event Definition

31

 

 

8.1.2

Serious Adverse Event Definition

31

 

8.2

Monitoring of Adverse Events and Period of Observation

32

 

8.3

Procedures for Recording and Reporting AEs and SAEs

32

 

8.4

Rules for Suspension of the Study

34

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

9.0

Statistical Procedures

34

 

9.1

Sample Size

35

 

9.2

Randomization, Stratification and Blinding

35

 

9.3

Populations for Analysis

35

 

 

9.3.1

Safety Population

35

 

9.4

Procedures for Handling Missing, Unused, and Spurious Data

35

 

9.5

Statistical Methods

35

 

 

9.5.1

Statistical Considerations

35

 

 

9.5.2

Baseline Comparisons

35

 

 

9.5.3

Fractures and BMD Analysis

36

 

 

9.5.4

Safety Analysis

36

 

 

9.5.5

Procedures for Reporting Deviations to Original Statistical Analysis Plan

36

 

9.6

Data Oversight

36

 

 

9.6.1

Central Review of Radiographs and DXA Scans

36

 

 

 

10.0

ADMINISTRATIVE REQUIREMENTS

37

 

10.1

Good Clinical Practice

37

 

10.2

Ethical Considerations

36

 

10.3

Subject Information and Informed Consent

37

 

10.4

Protocol Compliance

37

 

10.5

Case Report Form Completion

38

 

10.6

Source Documents

38

 

10.7

Study Monitoring

38

 

10.8

On-Site Audits

39

 

10.9

Drug Accountability

39

 

10.10

Record Retention

39

 

10.11

Study Termination

39

 

10.12

Liability and Insurance

40

 

 

 

11.0

USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

40

 

11.1

Use of Information

40

 

11.2

Publication

41

 

 

 

12.0

INVESTIGATOR AGREEMENT

42

 

 

 

13.0

References

43

 

 

 

14.0

APPENDICES

44

 

14.1

Schedule of Visits and Procedures

45

 

14.2

Suggested Schedule of Events and Procedures by Study Visit

47

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

 

14.3

Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria

1

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

LIST OF ABBREVIATIONS

 

Abbreviation

 

Term

°C

 

Degree Celsius

°F

 

Degree Fahrenheit

µg

 

Microgram

µmol

 

Micromole

AE

 

Adverse event

ALT

 

Alanine aminotransferase

AST

 

Aspartate aminotransferase

BMD

 

Bone mineral density

BMI

 

Body mass index

bpm

 

Beats per minute

BSAP

 

Bone-specific alkaline phosphatase

BUN

 

Blood urea nitrogen

cm

 

Centimeter

CPK

 

Creatine phosphokinase

CRF

 

Case report form

CRO

 

Contract research organization

CTX

 

C-telopeptides of type 1 collagen crosslinks (serum)

DXA

 

Dual energy x-ray absorptiometry

ECG

 

Electrocardiogram

eCRF

 

Electronic case report form

FDA

 

Food and Drug Administration

g

 

Gram

GCP

 

Good clinical practice

GGT

 

Gamma-glutamyltranspeptidase

GLP

 

Good laboratory practice

GMP

 

Good manufacturing practice

hPTH1R

 

Human parathyroid hormone receptor 1

ICH

 

International Conference on Harmonization

IEC

 

Independent ethics committee

IRB

 

Institutional review board

ITT

 

Intent-to-treat

IU

 

International unit

IV

 

Intravenous

IVRS

 

Interactive voice response system

kg

 

Kilogram

L

 

Liter

LDH

 

Lactate dehydrogenase

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Abbreviation

 

Term

MCH

 

Mean corpuscular hemoglobin

MCHC

 

Mean corpuscular hemoglobin concentration

MCV

 

Mean corpuscular volume

MedDRA

 

Medical dictionary for regulatory activities

µL

 

Microliter

mg

 

Milligram

mL

 

Milliliter

mmHg

 

Millimeter of mercury

msec

 

Millisecond

NPO

 

Nothing by mouth

ng

 

Nanogram

ONJ

 

Osteonecrosis of the jaw

pg

 

Picogram

PINP

 

N-terminal propeptide of type I procollagen

PT

 

Prothrombin time

PTH

 

Parathyroid hormone

PTHrP

 

Parathyroid hormone related peptide

PTT

 

Partial thromboplastin time

PUBs

 

Upper respiratory perforations, ulcers and bleeds

QT

 

Total depolarization and repolarization time

QTc

 

Total depolarization and repolarization time corrected with heart rate

RBC

 

Red blood cell

rhPTH

 

Recombinant hPTH

SAE

 

Serious adverse event

SC

 

Subcutaneous

SD

 

Standard deviation

SERMs

 

Selective estrogen receptor modulators

SOP

 

Standard operating procedure

ULN

 

Upper Limit of Normal

WBC

 

White blood cells

WHO

 

World Health Organization

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

1.0        INTRODUCTION

 

1.1                         Background Information

 

Osteoporosis is a systemic skeletal disease characterized by low bone mass and
microarchitectural deterioration of bone tissue which leads to enhanced
fragility and increased risk of fractures (Rizzoli, 2001).  It is estimated that
over 200 million people worldwide have osteoporosis (Reginster, 2006) and
osteoporosis causes more than 8.9 million fractures worldwide, of which more
than 4.5 million occur in the Americas and Europe (WHO Scientific Group, 2007). 
The vast majority of osteoporotic fractures occur in elderly women and incidence
increases markedly with age.  Most fractures occur at the spine, wrist and hip. 
Of these, hip fractures carry the highest morbidity and mortality.  In 1990, the
total number of hip fractures in men and women was estimated to be 1.26 million
worldwide, and it is estimated that this number will increase to 3.6 million by
2025 and to 4.5 million by 2050 (Gullberg, 1997).

 

Subject enrolled in this Extension Study will have completed 18 months of
treatment with BA058 Injection 80 µg/Placebo.  BA058 is a synthetic 34 amino
acid analog of PTHrP, with molecular modifications of specific amino acids, and
is under clinical development for the prevention of fractures in postmenopausal
women with severe osteoporosis who are at a risk for fracture.  BA058 shows
particular potential for reversing bone loss at both the spine and the hip, the
site of the most debilitating osteoporotic fractures in elderly women.  BA058 is
a synthetic analog of PTHrP (1-34) designed to give a greater anabolic effect
than hPTH.  Initial in vitro and in vivo studies identified BA058 as displaying
bone anabolic properties without a significant hypercalcemic effect.  In humans,
BA058 has different pharmacokinetics (PK) and pharmacodynamics (PD) properties
than hPTH(1-34) and has been shown in a Phase 2 study (BA058-05-002) to have
similar or greater efficacy in restoring bone mineral density (BMD) in
individuals with osteoporosis than hPTH(1-34).  Overall, BA058 has been well
tolerated in previous studies.

 

This is an open-label Extension of Study BA058-05-003.  Enrollment requires
previous participation in, and successful completion of, 18 months of treatment
with BA058 Injection 80 µg/Placebo in Study BA058-05-003.  The purpose of this
extension is to accumulate longer-term safety, fracture, and BMD data in
subjects who receive six months of standard-of-care osteoporosis treatment,
including treatment with alendronate, following 18 months of treatment with
blinded BA058/Placebo treatment.  Alendronate, a bisphosphonate, is approved and
marketed world-wide for the treatment and prevention of osteoporosis in
postmenopausal women.

 

1.2                               Drug Under Study

 

1.2.1                     Efficacy of Alendronate

 

Alendronate is a bisphosphonate that acts as a specific inhibitor of
osteoclast-mediated bone resorption.  Bisphosphonates are synthetic analogs of
pyrophosphate that bind to the hydroxyapatite found in bone.  At the cellular
level, alendronate shows preferential localization to sites of bone resorption,
specifically under osteoclasts.  The osteoclasts adhere normally to the bone
surface but lack the ruffled border that is indicative of active resorption.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Alendronate does not interfere with osteoclast recruitment or attachment, but it
does inhibit osteoclast activity. (Fosamax Package Insert)

 

Bisphosphonates including alendronate are widely used to treat osteoporosis.  In
animal models, minipigs treated with alendronate exhibited a direct correlation
between cancellous bone volume and bone strength (Lefage 1995).  In primates,
treatment with alendronate increased the strength of cancellous bone between 44
and 100% (the effect was dose dependent) when compared to vehicle, and also
increased bone mass (Balena 1993).  In dogs, this increase in bone mass occurred
without causing abnormalities in bone modeling of bone structure (Balena, 1996).

 

In postmenopausal women, alendronate has been demonstrated to increase bone
mineral density, decrease bone turnover and reduce the risk of fracture among
women with osteoporosis (Tucci, 1996; Devogelaer, 1996; Liberman, 1995).  The
therapeutic effects on bone density, remodeling and fracture prevention persist
following daily treatment at an oral dose of 10 mg for up to 10 years (Bone,
2004).  Studies have demonstrated that sequential treatment of osteoporosis with
one year of treatment with PTH followed by one year of treatment with
alendronate resulted in an increase in vertebral bone density that was
considerably greater than previously reported for alendronate alone (Rittmaster,
2000).  In subjects receiving PTH(1-84) followed by alendronate, there were
significant increases in BMD, in particular trabecular spine, when compared to
PTH(1-84) followed by placebo (31% vs. 14%, p<0.001) (Black, 2005).

 

1.2.2                     Safety of Alendronate Sodium

 

According to the US package insert for Fosamax® (alendronate sodium), in studies
of up to five years duration, adverse experiences usually were mild and
generally did not require discontinuation of therapy.  In a three-year,
placebo-controlled, double blind study in which 196 subjects were treated with
10 mg/day, discontinuation due to any adverse experience occurred in 4.1% of
subjects treated with alendronate, and 6% of 397 subjects treated with placebo. 
The most frequently reported adverse event (occurring in >2% of subjects treated
with alendronate) in this study were abdominal pain, musculoskeletal pain,
nausea, dyspepsia, constipation, diarrhea, flatulence, headache and acid
regurgitation.

 

Alendronate may cause local irritation of the upper gastrointestinal mucosa. 
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and
esophageal erosions occasionally with bleeding and rarely followed by esophageal
stricture or perforation have been reported.  Osteonecrosis of the jaw (ONJ),
which can occur spontaneously, is generally associated with tooth extraction
and/or local infection with delayed healing, has been reported in subjects
taking alendronate.  For subjects requiring dental procedures, discontinuation
of alendronate therapy may reduce the risk for ONJ.

 

Atypical, low-energy, or low trauma fractures of the femoral shaft have been
reported in bisphosphonate-treated patients.  These fractures can occur anywhere
in the femoral shaft from just below the lesser trochanter to above the
supracondylar flare and are transverse or short oblique in orientation without
evidence of comminution.  Causality has not been established as these fractures
also occur in osteoporotic patients who have not been treated with
bisphosphonates.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Atypical femur fractures most commonly occur with minimal or no trauma to the
affected area.  They may be bilateral and many patients report prodromal pain in
the affected area, usually presenting as dull, aching thigh pain, weeks to
months before a complete fracture occurs.  A number of reports note that
patients were also receiving treatment with glucocorticoids (e.g. prednisone) at
the time of fracture.

 

Any patient with a history of bisphosphonate exposure who presents with thigh or
groin pain should be suspected of having an atypical fracture and should be
evaluated to rule out an incomplete femur fracture.  Patients presenting with an
atypical fracture should also be assessed for symptoms and signs of fracture in
the contralateral limb.  Interruption of bisphosphonate therapy should be
considered, pending a risk/benefit assessment, on an individual basis.

 

According to the Summary of Product Characteristics for alendronate from the
EMA, the following adverse experiences have been reported in alendronate treated
subject during clinical trials and/or post-marketing use:

 

Common:  Headache, abdominal pain, dyspepsia, constipation, diarrhea,
flatulence, esophageal ulcer, dysphagia, abdominal distension, acid
regurgitation and musculoskeletal pain.

 

Uncommon:  Nausea, vomiting, gastritis, esophagitis, esophageal erosions,
melena, rash, pruritus and erythema.

 

Rare:  Hypersensitivity reactions including urticarial and angioedema,
symptomatic hypocalcemia (often in association with predisposing conditions),
uveitis, scleritis, episcleritis, esophageal stricture, oropharyngeal
ulceration, upper gastrointestinal perforations, ulcers and bleeds (PUBs), rash
with photosensitivity, osteonecrosis of the jaw, atypical subtrochanteric and
diaphyseal femoral fractures and transient symptoms as in an acute-phase
response (myalgia, malaise and rarely, fever), typically associated with
initiation of treatment.

 

1.3                               Study Rationale and Selection of Doses

 

1.3.1                     Study Rationale

 

The purpose of the study is to provide longer term safety data, fracture data
and BMD data after six months of standard-of-care osteoporosis treatment,
including treatment with alendronate, in otherwise healthy ambulatory
postmenopausal women with severe osteoporosis who have previously received 18
months of blinded treatment with BA058 Injection or Placebo.

 

1.3.2                     Study Design

 

Subjects randomized to BA058 Injection 80 µg/Placebo, who have completed 18
months of treatment in Protocol BA058-05-003 and, who meet the
Inclusion/Exclusion criteria (Sections 4.2 and 4.3) are eligible to participate
in this study.  Subjects originally randomized to BA058 Injection 80 µg/Placebo
in Study BA058-05-003 and who are candidates for ongoing osteoporosis care, will
receive six months of daily open-label alendronate treatment at a dose of 10
mg/day.  Subjects who are sensitive to alendronate, or who are not candidates

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

for alendronate, may also participate in the study and be treated with an
alternative osteoporosis medication according to the Investigator.

 

1.3.3                     Study Population

 

The study population in this protocol is comprised of otherwise healthy
ambulatory postmenopausal women who:

 

1.              have participated in Study BA058-05-003,

2.              were randomized to either BA058 Injection 80 µg/Placebo,

3.              have completed the End-of-Treatment Visit (Visit 9 in Study
BA058-05-003), and

4.              have provided a new written informed consent for this protocol.

 

Subjects will not be enrolled if they experienced treatment-related SAE or were
withdrawn from Study BA058-05-003 for any reason.

 

1.3.4                     Selection of Endpoints

 

The fracture incidence; either clinically or radiologically determined, based on
clinical events or protocol-directed vertebral x-rays at Month 6 of this
Extension Study; will be tabulated.  In addition, BMD results from the six
months of treatment with alendronate will also be tabulated, with additional
tabular categories for results from the entire contiguous 24 months from
baseline of study BA058-05-003 through the end of Study BA058-05-005, as well as
the results during the 18 months of study BA058-05-003, for subjects who
eventually enter study BA058-05-005. Bone formation (PINP, osteocalcin, BSAP)
and resorption (CTX) markers will also be assessed.  The End-of-Treatment (Visit
9) evaluations for BMD, vertebral fracture, and non-vertebral fracture
assessments from BA058-05-003 will serve as the baseline evaluations in this
study.

 

Subjects will be monitored for safety events and will have safety assessments
performed at each study visit.  At the end of the study, at Month 6, BMD by DXA,
as well as clinical and radiologic assessment of the spine for assessment of
fractures will be performed.  Bone formation and resorption markers will also be
assessed at Month 6.  Further details of these assessments are in Section 7.0,
and in Appendix 14.1 and 14.2.

 

1.3.5                     Selection of Dose

 

The dose of alendronate (10 mg per day, oral) selected for this study is based
upon the recommended daily dose in the product’s prescribing information. 
Should an alternative treatment for osteoporosis be used, the dose and route of
administration will be according to that product’s prescribing information.

 

All enrolled subjects will also continue to receive calcium (500-1000 mg) and
vitamin D (400-800 IU) supplementation.

 

2.0        STUDY OBJECTIVES

 

The primary objective of this study is to evaluate data obtained following six
months of standard-of-care osteoporosis treatment, including treatment with
alendronate, in subjects who have previously received 18 months of blinded
treatment with BA058 Injection 80 µg/Placebo.  Safety will be evaluated with
clinical, laboratory and radiologic assessment.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Since it is anticipated that the majority of subjects will be treated with
alendronate, the study objectives are based upon this assumption.

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate in
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

3.0          INVESTIGATIONAL PLAN

 

3.1                               Overall Design and Study Plan

 

This study is an open-label extension of Study BA058-05-003.  Subjects and
Investigators who participate in Study BA058-05-005 will remain blinded to prior
treatment assignment as part of BA058-05-003.  At the End-of-Treatment visit
(Visit 9) for Study BA058-05-003, the possibility of participating in the
Extension Study will be discussed with subjects randomized to BA058 80
µg/Placebo.  The Extension Study will be comprised of standard-of-care
osteoporosis management, including six months of treatment with alendronate, if
appropriate.  In the month between Visit 9 and Visit 10, the Investigator will
review the results of the assessments performed at Visit 9, including a local
interpretation of BMD, and determine if alendronate, or an alternative therapy
is appropriate for the subject.  All subjects will continue to receive vitamin D
and calcium supplementation as they did in Study BA058-05-003.  The study design
is presented in Figure 2, below.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Figure 2:  Protocol BA058-05-005 Study Design

 

[g17732le09i001.jpg]

 

The total duration of study participation for an individual subject is
approximately six months from the initial treatment visit to final study
evaluations.  There are a total of three clinic visits during the course of the
study.

 

A brief summary of the study is provided below.  For a summary of the study
assessments to be performed, refer to Section 7.0 (Study Assessments) and to the
Schedule of Visits and Procedures (Appendix 14.1).  A more detailed description
of the study procedures on a by-visit basis is provided in Appendix 14.2
(Suggested Schedule of Events and Procedures by Study Visit).  A suggested order
of procedures is also provided in this schedule.

 

3.1.1                     Treatment Period

 

Subjects will enter into Study BA058-05-005 on Day 1, and Day 1 will also serve
as Visit 10 (the Follow-up Visit) for Study BA058-05-003.  The Informed Consent
must be signed prior to undergoing any BA058-05-005 study related procedures,
and may be signed at either Visit 9 or Visit 10 of Study BA058-05-003.  Subjects
who received BA058 Injection 80 µg/Placebo in Study BA058-05-003 will receive
six months of open-label oral alendronate treatment, or an alternative
osteoporosis treatment as part of this study (BA058-05-005).

 

If determined by the Investigator to be appropriate, treatment will be daily, by
oral administration of alendronate at a dose of 10 mg.  Should an alternative
treatment for osteoporosis be used, the dose and route of administration will be
according to that product’s prescribing information.  Subjects will be given a
weekly diary card to record missed doses of medication including calcium and
vitamin D.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

A total of three clinic visits are scheduled during the study (Day 1, Month 3,
and Month 6).

 

Subjects will be instructed to take their first dose of study drug for Study
BA058-05-005 in the morning on the day following their Day 1 visit (Day 2 of
this study).  Study subjects will continue calcium and vitamin D supplementation
during this study as was administered during BA058-05-003 (Section 6.1).

 

At Month 3, subjects will return to the clinic for medication resupply, subject
diary review and questioning as to their use of concomitant medications and the
occurrence of adverse events.

 

The Month 6 visit will be scheduled to occur after the last dose of alendronate,
at which time vital signs, ECG, and safety labs will be performed.  Vertebral
fractures will be determined clinically and via protocol directed Month 6 x-ray
evaluation; non-vertebral fractures will be determined clinically.  In addition,
subjects will undergo a DXA of the hip and spine (and wrist, if the subject was
enrolled in the wrist DXA sub-study in Study BA058-05-003), and have samples
drawn for bone markers and anti-BA058 antibodies.  Any adverse event or clinical
laboratory abnormality recorded at the Month 6 Visit will be monitored until it
has resolved, become chronic or stable.  Procedures are to be performed as
described in Section 7.0, Appendix 14.1 and Appendix 14.2.

 

4.0        SELECTION OF STUDY POPULATION

 

4.1                               Number of Subjects

 

Subjects who completed 18 months of treatment with either BA058 Injection 80
µg/Placebo in Study BA058-05-003 will be given the opportunity to participate in
the Extension Study at all participating centers.  Based on randomization to the
BA058 Injection 80 µg/Placebo arms in Study BA058-05-003, up to 1,600 subjects
may be entered into this study.

 

The specific inclusion and exclusion criteria for enrolling subjects in this
study are presented below in Sections 4.2 and 4.3, respectively.  Exceptions to
these criteria should occur infrequently and should be discussed in advance and
approved by the Sponsor Medical Monitor.

 

4.2                               Inclusion Criteria

 

Subjects must meet all of the following criteria to be eligible to participate
in this study:

 

1.                                      The subject was enrolled, randomized to
BA058 Injection 80 µg/Placebo and completed 18-months of blinded treatment
within Study BA058-05-003.

 

2.                                      The subject is no more than 33 days from
last study medication administration.

 

3.                                      The subject has read, understood, and
signed the written informed consent form for the Extension Study.

 

4.3                               Exclusion Criteria

 

Subjects with any of the following characteristics are not eligible to
participate in the study:

 

1.                                      Subjects who were withdrawn from Study
BA058-05-003 for any reason.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

2.                                      Subjects who experienced a
treatment-related SAE during Study BA058-05-003.

 

4.4                               Withdrawal of Subjects from the Study

 

Subjects will be informed that they have the right to withdraw from the study at
any time for any reason without prejudice to their medical care.

 

Consistent with the prior protocol, BA058-05-003, the Investigator must withdraw
subjects from the study prior at any time in the study for the following
reasons:

 

·             Treatment-related SAEs;

 

·             Refusal of treatment;

 

·             Refusal or inability to complete study procedures;

 

·             Lost to follow-up.

 

The Investigator should exercise his/her best judgment and also has the right to
withdraw subjects from the study during the study for any of the following
reasons:

 

·             ECOG Grade 3 or 4 adverse events [Refer to Appendix14.3];

 

·             A complex of adverse events which, in the judgment of the
Investigator justifies treatment cessation;

 

·             Serious intercurrent illness;

 

·             Non-compliance;

 

·             Protocol violations;

 

·             Administrative reasons.

 

If a subject is withdrawn or discontinued from the study, the reason for
withdrawal is to be recorded in the source documents and on the case report
form.  All subjects withdrawn prior to completing the study should be encouraged
to complete the Month 6 Visit including any outstanding radiologic assessment or
BMD assessment by DXA.

 

4.5                               Temporary Suspension of Treatment

 

The Investigator has the right to suspend treatment with alendronate without
withdrawal of the subject from the study.  Reasons for temporary suspension of
treatment may include a medical reason unrelated to an adverse event (e.g., a
planned procedure), or important social or administrative events.  The reason
for the suspension of treatment is to be documented in the electronic case
report form (eCRF) and in source documents.

 

When treatment with alendronate is restarted, the subject should resume
treatment with the next scheduled dose (as if treatment had not been
interrupted).

 

4.6                               Replacement of Subjects

 

Subjects who have been enrolled into the study and subsequently withdraw or drop
out of the study will not be replaced.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

5.0                         STUDY TREATMENTS

 

5.1                               Study Medications

 

Alendronate will be sourced locally.  Calcium and vitamin D will be provided by
the study centers, similar to their provision in Study BA058-05-003.

 

5.1.1                     Alendronate

 

Alendronate will be sourced locally at the expense of the Sponsor.

 

Subjects will receive daily oral alendronate at a dose of 10 mg beginning on Day
2 for six months.  Additional provisions for dosing of alendronate should be
followed based on the prescribing information.  Alendronate provided will be in
the approved, marketed formulation.  The alendronate may be generic
substitutable approved versions which contain different inactive ingredients,
but the amount of active free alendronate must be equivalent to 10 mg.

 

5.1.1.1           Restrictions on Alendronate Use

 

Subjects should not receive alendronate if they have the following
conditions/limitations:

 

·                                          Abnormalities of the esophagus and
other factors which delay espophageal emptying such as stricture or achalasia.

 

·                                          Inability to stand or sit upright for
at least 30 minutes.

 

·                                          Hypocalcemia.

 

·                                          Known history of hypersensitivity to
alendronate, alendronate excipients, or related compounds.

 

5.1.2                     Alternative Osteoporosis Medication

 

Any alternative treatment(s) for osteoporosis will be sourced locally at the
discretion of the Investigator.  The Sponsor and the Investigator will not
provide or be responsible for the costs of that alternative medication should
they be prescribed.

 

5.1.3                     Calcium and Vitamin D Supplements

 

Calcium and vitamin D supplements will be sourced locally and provided by the
sites at the expense of the Sponsor.

 

5.2                               Packaging, Labeling and Storage

 

Alendronate will not be relabeled for the study.

 

Any alternative osteoporosis medication will not be relabeled for the study.

 

Calcium and vitamin D supplements will not be relabeled for the study.

 

5.2.1                     Storage

 

Alendronate must be kept in a secure, limited-access storage area until
dispensed for use to a study subject.   Alendronate sodium should be stored in a
well-closed container at room temperature, 15-30ºC (59-86ºF).

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

The alternative osteoporosis medication will be stored by the subject according
to the instructions provided in the prescribing information and by the local
pharmacy where the medication is purchased.

 

Calcium and vitamin D supplements may be stored at room temperature.

 

5.3                               Treatment Assignment

 

All subjects who participate will continue to be identified by the same 7-digit
subject number that was assigned upon enrollment into Study BA058-05-003
throughout the study and on the eCRF.

 

5.4                               Study Medication Administration

 

5.4.1                     Alendronate Administration

 

Alendronate must be taken with water only (not mineral water) at least 30
minutes before the first food, beverage or medicinal product (including
antacids, calcium supplements and vitamins) of the day.  Other beverages
(including mineral water), food and some medicinal products are likely to reduce
the absorption of alendronate.

 

The following instructions should be followed exactly in order to minimize the
risk of esophageal irritation and related adverse reactions.

 

·                  Alendronate should only be swallowed after getting up for the
day with a full glass of water (not less than 200 mL or 7 fl. oz.).

·                  Subjects should only swallow alendronate whole.  Subjects
should not crush or chew the tablet or allow the tablet to dissolve in their
mouths because of a potential for oropharyngeal ulceration.

·                  Subjects should not lie down until after their first food of
the day.

·                  Subjects should not lie down for at least 30 minutes after
taking alendronate.

·                  Alendronate should not be taken at bedtime or before arising
for the day.

 

At the Month 3 visit, the unused alendronate tablets are to be returned to the
clinic and the subject will be supplied with additional alendronate.  At the
Month 6 visit, all unused alendronate tablets are to be returned to the study
site.

 

5.4.2                     Alternative Osteoporosis Medication Administration

 

If it is determined by the Investigator that an alternative medication to
alendronate is more appropriate for a particular subject, the dose and route of
administration will be according to the products prescribing information.

 

5.5                               Treatment Compliance

 

The study site personnel will perform drug accountability at each clinic visit
and review each subject diary (refer to Section 7.1.16).  Accountability will be
documented on the appropriate forms and subjects will be re-trained on
administration as appropriate.  All doses of study medication are to be
self-administered.

 

If a subject does not administer or take all study medication including vitamin
D or calcium, the reason for the missed dosing is to be recorded in source
documents and on the eCRF.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Returned, unused alendronate will be accounted for by the study site.

 

5.6                               Unblinding of Study Medication

 

Not applicable.

 

6.0        CONCOMITANT MEDICATIONS

 

6.1                               Concomitant Medications

 

Vitamin D and calcium supplements are required to be administered daily from Day
1 (continuing from Protocol BA058-05-003) until the Month 6 Visit.  Vitamin D
and calcium supplements will be administered in the following doses: 400-800
IU/day (Vitamin D) and 500-100mg/day (calcium), or at a dose to be determined by
the Investigator and agreed upon by the Sponsor Medical Monitor according to the
subjects need.  The doses and schedule of Vitamin D and calcium supplements,
which are part of the study medication protocol, should be adhered to and not be
changed other than for medical necessity.  The supplements should be taken in
the evening with or without food or as otherwise instructed by the Investigator.

 

For any required concomitant medication, such as statins or antihypertensives,
the subject must be on a stable dose at study entry and every effort should be
made to maintain a stable dose during study participation.

 

The occasional use of over-the-counter medications at approved doses (e.g.,
ibuprofen or acetaminophen) for headache or minor discomfort is allowed. 
Occasional short term (<3 months) use of corticosteroids for seasonal allergies
or asthma is also allowed.  These are to be recorded on the appropriate case
report form.  Subjects should not take any other medications, including
over-the-counter medications, herbal medications, or mega-doses of vitamins
during the study without prior approval of the Investigator.

 

If it becomes necessary for a subject to take any other medication during the
study, the specific medication(s) and indication(s) must be discussed with the
Investigator.  All concomitant medications taken during the course of the study
must be recorded in the Subject’s medical record or source document and
transcribed into the case report form.

 

6.2                               Prohibited Medications

 

Subjects who require treatment during the course of the study with either an
anticonvulsant (phenobarbital, phenytoin, carbamazepin or primidone) or chronic
treatment with any form of heparin will be discontinued.  Estrogens given as HRT
are allowed at entry into the study but cannot be initiated during the study
except for local low dose vaginal estrogen.

 

Drugs that may compromise renal function such as non-steroidal anti-inflammatory
drugs should be used with caution.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

7.0                         STUDY ASSESSMENTS

 

Subjects randomized to BA058 Injection 80 µg/Placebo in Study BA058-05-003 will
receive alendronate at a dose of 10 mg daily for six months, or an alternative
osteoporosis treatment at the discretion of the Investigator.

 

The assessments performed at each study visit are displayed in the Schedule of
Visits and Procedures in Appendix 14.1.  Appendix 14.2 provides a more detailed
schedule of the study procedures by study visit with a suggested order of
procedure conduct.  Exact procedures for centrifuging, storage, and shipping of
lab samples will be detailed in a separate document.  The actual time of each
blood collection will be recorded on the appropriate source documents and in the
eCRF.

 

Study-specific assessments are to be conducted only after the subject has
provided written informed consent to participate in this study.  The study
assessments are described in more detail in Section 7.1 below.

 

7.1                               Clinical Procedures/Assessments

 

7.1.1                     Informed Consent

 

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility
of participating in the Extension Study will be discussed with the subjects
randomized to BA058 80 µg/Placebo.  The Informed Consent must be signed prior to
undergoing any BA058-05-005 study related procedures, and may be signed at
either Visit 9 or Visit 10 of Study BA058-05-003.

 

7.1.2                     Medical History

 

The subject’s medical history will be updated from their last visit in Study
BA058-05-003, as necessary.  Any changes in medical history should be recorded
as an adverse event, as appropriate.

 

7.1.3                     Physical Examination

 

The physical exam from the End-of-Treatment visit (Visit 9) of Study
BA058-05-003 will be the baseline for this study (Day 1).  A physical exam will
also be performed at Month 6.

 

Interim or symptom-directed physical examinations may be performed at other
times at the discretion of the Investigator, if necessary, to evaluate adverse
events or clinical laboratory abnormalities.

 

7.1.4                     Vital Signs

 

Blood pressure, body temperature (ºC), pulse (bpm) and respiration rate (breaths
per minute) are to be measured and recorded at each study visit (Day 1, Month 3
and Month 6).  Only the Day 1 blood pressure assessments need be conducted as an
orthostatic measurement (See Section 7.1.5).

 

7.1.5                     Orthostatic Blood Pressure and Heart Rate

 

The Day 1 orthostatic blood pressure measurement for Study BA058-05-005 will
serve as the Visit 10 orthostatic blood pressure for Study BA058-05-003.  Blood
pressure (mmHg;

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

measured in the same arm at each visit) and pulse rate (bpm) will be measured
after five minutes in the supine position.  Immediately following this
measurement, blood pressure will be measured again after three minutes in the
standing position.

 

7.1.6                     Electrocardiogram

 

A twelve-lead supine electrocardiograms (ECGs) will be performed and the
following ECG parameters will be recorded: rhythm, heart rate, PR interval, QRS
duration and QT/QTc.

 

The Day 1 ECG measurement for Study BA058-05-005 will serve as the Visit 10 ECG
measurement for Study BA058-05-003.  An ECG will also be obtained at Month 6.

 

7.1.7                     Clinical Laboratory Evaluations

 

Clinical laboratory evaluations will be performed by a central laboratory. 
Prior to starting the study, the Sponsor (or its designee) will provide each
Investigator with copies of the appropriate laboratory certifications and normal
ranges for all laboratory parameters to be performed by that laboratory.

 

The majority of the blood and urinalysis samples are to be obtained under
fasting conditions (NPO for 8 hours; water is acceptable) in the morning of each
scheduled study visit prior to the administration of the study medication, the
exceptions are noted below.

 

All clinically significant laboratory abnormities indicating an adverse event
will be followed up by repeat testing and further investigated as necessary,
according to the judgment of the Investigator.

 

7.1.8                     Clinical Chemistry and Urinalysis (Dipstick)

 

Clinical chemistry and dipstick urinalysis will be performed on Day 1 and at
Month 6.  Urinalysis will be performed using samples freshly voided during the
clinic visit.  If there are positive findings noted on the dipstick, a urine
microscopic examination will be performed.  The following tests will be
performed:

 

Serum Chemistry

·      Sodium

 

·      Potassium

 

·      Chloride

 

·      Inorganic phosphorus

 

·      Albumin

 

·      Total protein

 

·      Glucose

 

·      Blood urea nitrogen (BUN)

 

·      Creatinine

 

·      Uric acid

 

·      Aspartate aminotransferase (AST)

 

·      Alanine aminotransferase (ALT)

 

·      Gamma-glutamyltranspeptidase (GGT)

 

·      Creatine phosphokinase (CPK)

 

·      Alkaline phosphatase

 

·      Total bilirubin

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

 

·      Lactate dehydrogenase (LDH)

 

·      Cholesterol

 

·      Triglycerides

 

·      Total calcium

Urinalysis

·      pH

 

·      Glucose

 

·      Protein

 

·      Ketones

 

·      Bilirubin

 

·      Blood

 

·      Urobilinogen

 

·      Specific gravity

 

·      Nitrite

 

·      Leukocytes

 

7.1.9                     Hematology

 

Hematology testing will also be performed on Day 1 and at Month 6.  The
following tests will be performed:

 

Hematology:

·      Hemoglobin

 

·      Hematocrit

 

·      WBC count with differential in absolute counts

 

·      RBC count

 

·      Mean corpuscular volume (MCV)

 

·      Mean corpuscular hemoglobin concentration (MCHC)

 

·      Mean corpuscular hemoglobin (MCH)

 

·      Platelet count

 

7.1.10              Coagulation

 

Coagulation testing will also be performed on Day 1 and at Month 6.  The
following tests will be performed:

 

 

·      Prothrombin time (PT)

 

·      Partial thromboplastin time (PTT)

 

7.1.11              24-Hour Urine Collection

 

The 24-hour urine collection is to be begun the day before the Day 1 and Month 6
visits.  Subjects are to be instructed to begin the urine collection by
discarding the first morning void (~6 a.m.) the day prior to the scheduled
clinic visit and to then collect their urine for 24 hours.  A final void is to
be collected at the end of the 24-hour period and the urine collection
transported to the clinic by the subject.  The 24-hour urinalysis will be used
to measure urinary calcium and urinary creatinine.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

7.1.12              Bone Mineral Density

 

All subjects will have bone mineral density measurements (BMD) taken via DXA at
Month 6.  The End-of-Treatment (Visit 9) bone mineral density tests for Study
BA058-05-003 will serve as the baseline BMD measurements for Study BA058-05-005.

 

DXAs will be performed on the hip (femoral neck) and spine (L1-4).  The spinal
DXA is to be taken in the postero-anterior (PA) projection with any subsequent
spinal DXA to be taken in the same projection.  Subjects who underwent wrist
DXAs in Study BA058-05-003 will also have wrist DXAs performed at Month 6.

 

7.1.13              Serum Markers of Bone Metabolism

 

Blood samples to measure bone markers will be taken on Day 1 and at Month 6. 
The results of the bone markers will be reported in the same subset of subjects
reported on for Study BA058-05-003.

 

The following markers of bone formation will be measured:

 

·                  Serum N-terminal propeptide of type I procollagen (PINP);

 

·                  Serum bone-specific alkaline phosphatase (BSAP);

 

·                  Serum osteocalcin.

 

 

The following marker of bone resorption will be measured:

 

·                  Serum C-telopeptides of type 1 collagen crosslinks (CTX).

 

7.1.14              Clinical and Radiologic Evaluation of Fractures

 

Subjects will undergo protocol directed antero-posterior and lateral radiographs
of the lumbar and thoracic spines at Month 6.  The End-of-Treatment (Visit 9)
clinical and radiological evaluation of fractures for Study BA058-05-003 will
serve as the baseline assessments for Study BA058-05-005.  Subjects will also be
clinically evaluated for non-vertebral fractures (wrist, hip, rib, etc.) that
occur de novo during the Treatment Period.

 

All radiographs will be viewed and assessed centrally by a blinded, independent
assessor (radiologist) on the basis of existing baseline and study-acquired
vertebral deformity.  Fractures will be assessed according to the severity scale
of Genant (1993).  A second blinded radiologist will confirm the assessment of
the first reviewer for all subject radiographs in which an incident fracture has
been identified.  In the case of any disagreement, a third consensus assessment
will be made to adjudicate the incident fracture.

 

Fractures identified during the study will not be recorded as AEs unless the
subject is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the subject’s underlying
osteoporosis.  All fractures (vertebral and non-vertebral) will be identified
and evaluated as part of the disease assessment and will be documented in the
case report forms and source documents.

 

7.1.15              BA058 Antibody Assessments

 

The occurrence of anti-drug antibodies will be assessed at the completion of the
study.  Serum samples will be drawn at Month 6.  Any positive subjects will be
retested at 6 months

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

and 12 months after completion of this study (BA058-05-005) under a separate
Safety Surveillance protocol.  Exact procedures for collection, preparation,
storage, and shipping of these samples will be detailed in a separate document. 
The actual time and date of each blood collection will be recorded on the
appropriate source document and in the eCRF.

 

7.1.16              Subject Diaries

 

A weekly diary will be completed by the subject beginning on the Day 1 visit and
continuing until the last day of Month 6.  This diary will capture missed doses
of vitamin D, calcium and alendronate or other osteoporosis medications.  The
weekly diary will be reviewed at each study visit.

 

7.1.17              Activity and Diet

 

Subjects who qualify for enrollment in the study will have no restrictions
placed on their usual level of activity or on their usual diet, unless directed
by the treating physician for medically justified reasons.

 

8.0                         ADVERSE EVENTS AND SAFETY EVALUATION

 

Timely, accurate, and complete reporting and analysis of safety information from
clinical studies are crucial for the protection of subjects, Investigators and
the Sponsor, and is mandated by Regulatory Agencies worldwide.  All clinical
trials sponsored by RADIUS will be conducted in accordance with Standard
Operating Procedures (SOPs) that have been established to conform to regulatory
requirements worldwide to ensure appropriate reporting of safety information.

 

8.1                         Definitions, Documentation, and Reporting

 

8.1.1                     Adverse Event Definition

 

An adverse event (AE) is any untoward medical occurrence in a subject
administered a pharmaceutical product, which does not necessarily have a causal
relationship with the treatment.  An AE can be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of the study drug, whether or not it is considered to be
study drug related.  This includes any newly occurring event or previous
condition that has increased in severity or frequency since the administration
of study drug.

 

8.1.2                     Serious Adverse Event Definition

 

A serious adverse event (SAE) is any adverse event, occurring at any dose and
regardless of causality that:

 

·                  Results in death.

 

·                  Is life-threatening.  Life-threatening means that the subject
was at immediate risk of death from the reaction as it occurred, i.e., it does
not include a reaction which hypothetically might have caused death had it
occurred in a more severe form.

 

·                  Requires in-patient hospitalization or prolongation of
existing hospitalization.  Hospitalization admissions and/or surgical operations
scheduled to occur during

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

the study period, but planned prior to study entry are not considered AEs if the
illness or disease existed before the subject was enrolled in the trial. 
Provided that the illness/disease did not deteriorate in an unexpected manner
during the trial (e.g., surgery performed earlier than planned).

 

·                  Results in persistent or significant disability/incapacity. 
Disability is defined as a substantial disruption of a person’s ability to
conduct normal life functions.

 

·                  Is a congenital anomaly/birth defect.  This includes any
anomaly detected at or after birth, or any anomaly that results in fetal loss.

 

·                  Is an important medical event.  An important medical event is
an event that may not result in death, be life-threatening, or require
hospitalization, but may be considered an SAE when, based upon appropriate
medical judgment, it may jeopardize the subject and may require medical or
surgical intervention to prevent one of the outcomes listed in the definitions
for SAEs.  Examples of such medical events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood dyscrasias
or convulsions that do not result in in-patient hospitalization, or the
development of drug dependency or drug abuse.

 

Clarification should be made between the terms “serious” and “severe” since they
are not synonymous.  The term “severe” is often used to describe the intensity
(synonym: severity) of a specific event (as in mild, moderate, or severe
myocardial infarction); the event itself, however, may be of relatively minor
medical significance (such as a severe headache).  This is not the same as
“serious,” which is based on subject/event outcome or action criteria described
above and are usually associated with events that pose a threat to a subject’s
life or functioning.  A severe adverse event does not necessarily need to be
considered serious.  For example, persistent nausea of several hours duration
may be considered severe nausea but not an SAE.  On the other hand, a stroke
resulting in only a minor degree of disability may be considered mild, but would
be defined as an SAE based on the above noted criteria.  Seriousness (not
severity) serves as a guide for defining regulatory reporting obligations.

 

8.2                         Monitoring of Adverse Events and Period of
Observation

 

All AEs will be monitored until they are resolved or have become chronic or
stable.  AEs and SAEs will be recorded on the case report forms starting from
the time of subject entry from Day 1 of the study until the final study visit
(Month 6).  Any SAEs that occur at any time after completion of the study, which
the Investigator considers to be related to study drug, must be reported to the
Sponsor or its designee.

 

8.3                         Procedures for Recording and Reporting AEs and SAEs

 

All adverse events spontaneously reported by the subject and/or in response to
an open question from study personnel or revealed by observation, physical
examination or other diagnostic procedures must be recorded in the source
document and on the appropriate page of the case report form.  Any clinically
relevant deterioration in laboratory assessments or other clinical findings is
considered an adverse event and must be recorded on the appropriate pages of the
case report form.  When possible, signs and symptoms indicating a common
underlying pathology should be noted as one comprehensive event.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

All SAEs that occur during the course of the study, as defined by the protocol,
must be reported by the Investigator to the Study Safety Officer by completing
and transmitting the SAE Form within one working day from the point in time when
the Investigator becomes aware of the SAE.  In addition, all SAEs including all
deaths, which occur up to and including 30 days after administration of the last
dose of study drug, must be reported to the Study Safety Officer within one
working day.  All SAEs and deaths must be reported whether or not considered
causally related to the study drug.  SAE forms will be provided to the study
site.  The information collected will include a minimum of the following:
Subject number, a narrative description of the event, and an assessment by the
Investigator as to the intensity of the event, and relatedness to study drug. 
Follow-up information on the SAE may be requested by the CRO, the Study Safety
Officer or the Sponsor Medical Monitor.  Contact information for reporting SAEs
to the Study Safety Officer is provided on the SAE form.

 

Study Safety Officer Contact Information

 

PLEASE SEE SERIOUS ADVERSE EVENT REPORTING FORM FOR DETAILED REPORTING OF SAEs,
INCLUDING CONTACT INFORMATION (e.g., FAX, EMAIL OR TELEPHONE CONTACT NUMBERS)

 

It is the responsibility of the Investigator to promptly notify the
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all
serious adverse drug reactions involving risk to human subjects in accordance
with the requirements of the IRB/IEC.  An unexpected event is one that is not
reported in the Investigator’s Brochure.

 

Planned hospital admissions or surgical procedures for an illness or disease
that existed before the subject was enrolled in the trial or before study drug
was given are not to be considered AEs unless they occur at a time other than
the planned date.

 

Fractures identified during the study are not to be recorded as AEs unless the
subject is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the subject’s underlying
osteoporosis.  All fractures will be identified and evaluated as part of the
disease assessment and will be documented in the case report forms and source
documents.

 

For both serious and non-serious adverse events, the Investigator must determine
the intensity of the event and the relationship of the event to study drug
administration.

 

Intensity for each AE will be defined according to the following criteria:

 

Intensity

 

Definition

Mild

 

Awareness of sign or symptom, but easily tolerated.

Moderate

 

Discomfort enough to cause interference with normal daily activities.

Severe

 

Inability to perform normal daily activities

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

If the intensity of an adverse event changes within a day, the maximum intensity
should be recorded.  If the intensity changes over a longer period of time, the
changes should be recorded as separate events (having separate onset and stop
dates for each intensity).

 

Relationship to study drug administration will be determined by the Investigator
according to the following criteria:

 

Relationship

 

Definition

 

None

 

No relationship between the event and the administration of study drug. The
event is related to other etiologies, such as concomitant medications or
subject’s clinical state.

 

 

 

 

 

Unlikely

 

The current state of knowledge indicates that a relationship to study drug is
unlikely or the temporal relationship is such that study drug would not have had
any reasonable association with the observed event.

 

 

 

 

 

Possible

 

A reaction that follows a plausible temporal sequence from administration of the
study drug and follows a known response pattern to the suspected study drug. The
reaction might have been produced by the subject’s clinical state or other modes
of therapy administered to the subject.

 

 

 

 

 

Probable

 

A reaction that follows a plausible temporal sequence from administration of the
study drug and follows a known response pattern to the suspected study drug. The
reaction cannot be reasonably explained by the known characteristics of the
subject’s clinical state or other modes of therapy administered to the subject.

 

 

For the purpose of safety analyses, all AEs that are classified with a
relationship to study medication administration of possible or probable will be
considered treatment-related events.

 

8.4                         Rules for Suspension of the Study

 

As this is an Extension Study using standard-of-care management of osteoporosis,
including products approved for treatment, it is not anticipated that the study
will need to be suspended, and therefore, suspension rules are not assigned.  In
the event that the prior study (Study BA058-05-003) is suspended, the
circumstances of the Study BA058-05-003 suspension will be considered to
determine if this study, Study BA058-05-005, should be suspended as well.

 

9.0                         STATISTICAL PROCEDURES

 

The primary objective of this study is to evaluate data obtained following six
months of standard-of-care osteoporosis treatment, including treatment with
alendronate, in subjects who have previously received 18 months of blinded
treatment with BA058 Injection 80 µg/Placebo.  Safety data will be obtained with
clinical, laboratory and radiologic assessment.  Since it is anticipated that
the majority of the subjects will be treated with alendronate, the study
objectives are based upon this assumption.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate of
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

9.1                         Sample Size

 

As this is an Extension study, no formal sample size analysis was performed for
this study.  Study data will be tabulated and summarized.

 

9.2                         Randomization, Stratification and Blinding

 

Osteoporosis treatment will be open label and no randomization is required.

 

9.3                         Populations for Analysis

 

All analyses and data summaries will be presented for the Safety Population.

 

9.3.1                     Safety Population

 

The Safety Population is comprised of all subjects who qualify on the basis of
Study BA058-05-003 and provide informed consent to enroll in this Extension
Protocol.

 

9.4                         Procedures for Handling Missing, Unused, and
Spurious Data

 

All available data will be included in the data listings and tabulations. Where
appropriate, imputations of values for missing data will be performed using last
observation carried forward and specified in the Statistical Analysis Plan.  All
data recorded on the CRF will be included in the data listings that will
accompany the clinical study report.

 

9.5                         Statistical Methods

 

9.5.1                     Statistical Considerations

 

Statistical analysis will focus on longer term safety, fracture incidence,
including vertebral fracture and BMD change following six months of
standard-of-care osteoporosis treatment in subjects who have previously received
18 months of blinded treatment with BA058 Injection 80 µg/Placebo.

 

9.5.2                     Baseline Comparisons

 

Baseline characteristics, medical history, physical examination, vital signs and
ECG, will be summarized using standard descriptive statistics.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

9.5.3                     Fractures and BMD Analysis

 

All specified endpoints will be summarized by treatment group and study period
using standard descriptive statistics (n, mean, SD, median, minimum, maximum, or
n and %, as appropriate).  The fracture incidence and BMD results from the
additional six months of treatment with alendronate will be tabulated, with
additional tabular categories for results from the entire contiguous 24 months
from the baseline of Study BA058-05-003, for subjects who eventually enter study
BA058-05-005.  These descriptive analyses will be conducted on all subjects with
baseline and post-baseline data.

 

9.5.4                     Safety Analysis

 

Data will be summarized and tabulated based on the enrolled population for this
Extension protocol.  All subjects enrolled in the Extension protocol will be
included in the safety analysis that will be performed on the following
parameters:

 

·                  Incidence and severity of AEs;

 

·                  Pathological changes in hematology, chemistry and urinalysis
data based on normal ranges supplied by the clinical laboratory, if applicable;

 

·                  Fracture incidence either clinically or radiologically
determined as part of the Extension protocol.

 

Safety assessments for changes in physical examination, vital signs, ECG, and
laboratory tests will be descriptively summarized by treatment and study
periods.  The results of anti-BA058 testing will be summarized.  Concomitant
medication classes will be categorized using World Health Organization (WHO)
drug dictionary and summarized by number and percent of subjects using each
class by treatment group.  All treatment emergent adverse events (TEAEs) will be
coded for system organ class (SOC) and preferred term (PT) using MedDRA and the
number (%) of subjects experiencing each AE (SOC/PT) will be summarized by
treatment, relationship to treatment, and severity.  All serious adverse events
(SAE) will be listed and the number (%) of subjects with an SAE presented by
treatment group.

 

9.5.5                     Procedures for Reporting Deviations to Original
Statistical Analysis Plan

 

All deviations from the original statistical analysis plan will be provided in
the final clinical study report.

 

9.6                         Data Oversight

 

9.6.1                     Central Review of Radiographs and DXA Scans

 

All radiographs will be viewed and assessed by a blinded, independent assessor
(radiologist) on the basis of existing baseline and study-acquired vertebral
deformity, and fractures will be assessed according to the method of Genant.  A
second blinded radiologist will review the assessment of the first reviewer for
all subject radiographs in which an incident fracture has been identified.  In
the case of any disagreement, a third consensus assessment will be made to
adjudicate the incident fracture.  All study DXA scans will also be evaluated
centrally by a blinded independent reviewer.  The primary objective of the
independent review is to provide

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

objective data to determine the treatment benefit as demonstrated on the
pertinent radiologic and clinical data associated with this study.

 

10.0                  ADMINISTRATIVE REQUIREMENTS

 

10.1                  Good Clinical Practice

 

This study will be conducted in accordance with the International Conference on
Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate
regulatory requirements.  The Investigator will be thoroughly familiar with the
appropriate use of the study medication as described in the protocol and the
Investigator’s Brochure.  Essential clinical documents will be maintained to
demonstrate the validity of the study and the integrity of the data collected. 
The Investigator/institution should establish master files at the beginning of
the study which will be maintained and updated during the study and retained
thereafter according to the appropriate regulations.

 

10.2                  Ethical Considerations

 

The study will be conducted in accordance with ethical principles founded in the
Declaration of Helsinki.  The Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) will review all appropriate study documentation in order
to safeguard the rights, safety and well-being of the subjects.  The study can
only be conducted at study sites where IRB/IEC approval has been obtained.  The
protocol, informed consent form, Investigator’s Brochure, advertisements (if
applicable), and all other forms of information given to subjects will be
provided to the IRB/IEC by the Investigator.  In addition, reports on the
progress of the study will be submitted to the IRB/IEC by the Investigator at
the appropriate intervals.

 

10.3                  Subject Information and Informed Consent

 

Each subject (or a legally authorized representative) must give written informed
consent prior to any new study-specific procedures being conducted.   It is the
responsibility of the Investigator to ensure written informed consent is
obtained from each subject participating in this study after an explanation of
the objectives, methods, discomforts and potential risks of the study has been
provided.  The Investigator (or study personnel) must also explain to each
subject that he/she is free to refuse participation in the study or to withdraw
from it at any time.  Each subject will also be told that his/her records may be
examined by competent authorities and authorized persons but that personal
information will be treated as strictly confidential and will not be publicly
available.

 

The informed consent form must be in accordance with the Declaration of
Helsinki, ICH and GCP guidelines, and be approved by the Sponsor and the
IRB/IEC.  State or local laws may require additional information.  Each subject
(or his/her legally authorized representative) must sign and be given a copy of
the informed consent form.  Each subject’s signed informed consent form must be
maintained by the Investigator and be readily available for review by the
Sponsor (or its designee) or the Regulatory Authorities.

 

10.4                  Protocol Compliance

 

The Investigator will conduct this study in compliance with the protocol
provided by the Sponsor and given approval/favorable opinion by the IRB/IEC and
the appropriate

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Regulatory Authority(ies).  Changes to the protocol should not be made without
agreement of the Sponsor Medical Monitor.  All changes to the protocol will
require IRB/IEC approval prior to implementation, except when necessary to
eliminate an immediate hazard to study subjects or when the change involves only
logistical or administrative aspects of the study (e.g., change in Sponsor
Medical Monitor or telephone number).  The IRB/IEC may provide, if applicable
regulations permit, expedited review and approval/favorable opinion for minor
changes in ongoing studies.  The Sponsor will submit all protocol changes to the
appropriate Regulatory Authority in accordance with the governing regulations.

 

In situations requiring a departure from the protocol, the Investigator or other
physician in attendance will contact the Sponsor Medical Monitor by telephone,
e-mail or fax.  If possible, this contact will be made before implementing any
departure from the protocol.  In all cases, contact with the Sponsor Medical
Monitor must be made as soon as possible in order to review the situation and
agree on an appropriate course of action.  The case report form and source
document will describe any departure from the protocol and the circumstances
requiring it.

 

10.5                  Case Report Form Completion

 

eCRFs will be developed to collect information obtained during this study.  It
is the Investigator’s responsibility to ensure that the e-CRFs are completed for
each subject enrolled in this study and for the accuracy, completeness,
legibility and timeliness of the data reported in each e-CRF.  Data for subjects
who are screened but not enrolled into the study because they do not meet study
criteria or do not complete all screening procedures, should be recorded in the
e-CRF.

 

eCRFs will be completed and any corrections of data will be made according to
procedures provided by the Sponsor (or designee).

 

10.6                  Source Documents

 

Source documents are defined as original documents, data and records.  This may
include hospital records, clinical and office charts, laboratory
data/information, work sheets, subjects’ diaries or evaluation checklists,
pharmacy dispensing and other records, recorded data from automated instruments,
microfiches, photographic negatives, microfilm or magnetic media, ECG printouts,
and/or x-rays.

 

The Investigator(s)/institution(s) will permit trial-related monitoring,
audits, IRB/IEC review, and regulatory inspection(s), providing direct access to
source data documents.

 

10.7                  Study Monitoring

 

The Sponsor (or its designee) will ensure that the study is monitored in
accordance with ICH-GCP Guidelines.  Monitoring is the act of overseeing the
progress of a clinical trial and of ensuring that it is conducted, recorded, and
reported in accordance with the protocol, standard operating procedures, Good
Clinical Practice, and the applicable regulatory requirements and that the study
data are accurate, complete and verifiable from source data.  All study
documentation and other source data will be made available to the Sponsor (or
its designee), the IRB and to Regulatory Authorities for inspection upon
request.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

10.8                  On-Site Audits

 

Representatives of the IRB or the Sponsor (or designee) may visit the study site
to carry out an audit of the study in compliance with regulatory guidelines and
company policy.  Such audits will require access to all study records including
source documents, CRFs, and other study documents.  Direct access to these study
records must be guaranteed by the Investigator, who must provide support for
these activities at all times.

 

Similar auditing procedures may also be conducted by agents of any Regulatory
Authority reviewing the results of this study.  The Investigator/institution
should immediately notify the Sponsor if they have been contacted by a
Regulatory Authority concerning an upcoming inspection.

 

10.9                  Drug Accountability

 

Accountability for the study medication at the study site is the responsibility
of the Investigator.  Drug accountability will be performed only on alendronate,
calcium and vitamin D.  The Investigator will ensure that the study medication
is used only in accordance with this protocol.  Where allowed, the Investigator
may choose to assign some of the study medication accountability
responsibilities to qualified study personnel.

 

Study medication accountability records indicating the delivery date to the
study site, inventory at the study site and dispensing/use will be maintained. 
These records will adequately document that the study medications were dispensed
and returned as specified in the protocol.  Accountability records will include
dates, quantities, and subject numbers.  The Sponsor (or its designee) will
review study medication accountability records at the study site on an ongoing
basis during the study.  All used and unused study medication must be
inventoried, accounted for, and returned to the Sponsor (or its designee) for
destruction.  Records of disposal must be maintained with the study records.

 

10.10           Record Retention

 

The Investigator will maintain all study records according to ICH/GCP and
applicable regulatory requirements.  Essential documents must be retained for
two years after the final marketing approval in an ICH region or at least two
years have elapsed since the discontinuation of clinical development of the
study medication.  It is the responsibility of the Sponsor to inform the
Investigator of when these documents can be destroyed.  In addition, all subject
medical records and other source documentation will be kept for the maximum time
permitted by the hospital, institution or medical practice.

 

The Investigator/institution will take measures to prevent accidental or
premature destruction of these documents.  If the responsible Investigator
retires, relocates, or for other reasons withdraws from the responsibility of
keeping the study records, custody must be transferred to a person who will
accept the responsibility.  The Sponsor must be notified in writing of the name
and address of the new custodian.

 

10.11           Study Termination

 

This study may be terminated at any time by the Sponsor if there is sufficient
reasonable cause.  Circumstances that may warrant termination include, but are
not limited to:

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

·                  Determination of unexpected, significant, or unacceptable
risk to subjects.

 

·                  Failure of enrollment

 

·                  Administrative reasons

 

·                  Plans to modify, suspend or discontinue the development of
the study drug.

 

In addition, individual study sites may be terminated from study participation
for reasons including, but not limited to the following:

 

·                  Failure to enter subjects at an acceptable rate.

 

·                  Insufficient adherence to protocol requirements.

 

·                  Incomplete and/or non-evaluable data.

 

In all cases, the terminating parties will provide written notification
documenting the reason for study termination to all the relevant parties.

 

Should the study or an individual site be prematurely closed, all study
materials (completed, partially completed, and blank CRFs, study drug, etc.)
must be returned to the Sponsor (or its designee).

 

10.12           Liability and Insurance

 

The Sponsor has subscribed to an insurance policy covering, in its terms and
provisions, its legal liability for injuries caused to participating persons and
arising out of this research performed strictly in accordance with the
scientific protocol as well as with applicable law and professional standards.

 

11.0                  USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

 

11.1                  Use of Information

 

All information regarding BA058 supplied by the Sponsor (or its designee) to the
Investigator is privileged and confidential information.  The Investigator
agrees to use this information to accomplish the study and will not use it for
other purposes without prior consent from the Sponsor.

 

The information developed during the conduct of this clinical study is also
considered confidential and will be used by the Sponsor in connection with the
development of BA058.  This information may be disclosed as deemed necessary by
the Sponsor to other clinical Investigators, other pharmaceutical companies, and
to Regulatory Authorities.  To allow for the use of the information derived from
this study and to ensure complete and thorough analysis, the Investigator is
obligated to provide the Sponsor (or its designee) with complete study results
and all data developed in this study and to allow direct access to source
data/documents for study-related monitoring, audits, IRB/IEC review, and
regulatory inspection.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

11.2                  Publication

 

One publication of the study data is planned.  A Publications Committee composed
of Investigators participating in the study and representatives from the Sponsor
as appropriate will be formed to oversee the publication of the study results,
which will reflect the experience of all participating study centers.

 

Subsequently, individual Investigators may publish results from the study in
compliance with their agreement with the Sponsor.  A pre-publication manuscript
must be provided to the Sponsor at least 30 days prior to the submission of the
manuscript to a publisher.  Similarly, the Sponsor will provide any company
prepared manuscript to the Investigators for review at least 30 days prior to
submission to a publisher.

 

The Investigator shall comply with the policy of the Sponsor regarding
confidential or proprietary information in any such paper and agrees to withhold
publication of same for an additional 60 days in order to permit the Sponsor to
obtain patent or other proprietary rights protection, if the Sponsor deems it
necessary.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

12.0                        INVESTIGATOR AGREEMENT

 

To be completed by the Investigator

 

I have read Protocol BA058-05-005: “An Extension Study to Evaluate Six Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-003”.

 

I agree to conduct the study as detailed herein and in compliance with ICH
Guidelines for Good Clinical Practice and applicable regulatory requirements and
to inform all who assist me in the conduct of this study of their
responsibilities and obligations.

 

The signature below constitutes my agreement to the contents of this protocol.

 

 

 

 

 

Signature of Principal Investigator

Date

 

 

 

 

Principal Investigator (print)

 

 

 

 

 

Signature of Sponsor’s Medical Officer (where applicable)

 

 

 

 

 

 

 

 

Louis Brenner, MD

Date

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

13.0                  REFERENCES

 

EMEA. Guideline on the evaluation of medicinal products in the treatment of
primary osteoporosis. 2007.

 

FDA. Guidelines for preclinical and clinical evaluation of agents used in the
prevention or treatment of postmenopausal osteoporosis. 1994.

 

FDA. Draft guidance:  Development of parathyroid hormone for the prevention and
treatment of osteoporosis. 2000.

 

Genant HK, Wu CY, van KC, and Nevitt MC. Vertebral fracture assessment using a
semiquantitative technique. 1993;  J Bone Miner Res 8:1137-1148.

 

Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance.
U.S.Department of Health and Human Services, Food and Drug Administration.
April 1996.

 

Gullberg B, Johnell O, Kanis JA.  World-wide projections for hip fracture. 
Osteoporos Int 1997, 7:407-413.

 

Martin TJ.  Osteoblast-derived PTHrP is a physiological regulator of bone
function.  J Clin Inv 2005;115(9):2322-2324.

 

Miao D, He B, Jiang Y, Kobayashi T, Soroceanu MA, Zhao J, Su H, Tong X, Amizuka
N, Gupta A, Genant HK, Kronenberg HM, Goltxman D, Karaplis AC. 
Osteoblast-derived PTHrP is a potent endogenous bone metabolic agent that
modifies the therapeutic efficacy of administered PTH 1-34.  J Clin Inv
2005;115(9):2402-2411.

 

Reginster JY, Burlet N.  Osteoporosis: still increasing prevalence.  Bone 2006,
38(Suppl 1):S4-9.

 

Rizzoli R, Bonjour JP, and Ferrari SL. Osteoporosis, genetics and hormones. J
Mol Endocrinol 2001; 26:79-94.

 

Rosen CJ. Clinical practice.  Postmenopausal osteoporosis. N Engl J Med 2005;
353:595-603.

 

Schluter KD.  PTH and PTHrP: Similar structures but different functions.  News
Physiol Sci 1999;14:243-249.

 

WHO Scientific Group on the assessment of osteoporosis at primary health care
level.  World Health Organization Summary Meeting Report 2007.

 

World Medical Association Declaration of Helsinki. The World Medical
Association, Inc. 2008.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

14.0                                                APPENDICES

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

14.1                  Schedule of Visits and Procedures

 

 

 

Visit

 

1

 

2

 

3

 

Study Day/Month:

 

Visit 10 003/
Visit 1(1) 005

 

Month 3

 

Month 6

 

 

Day

 

1

 

90

 

180

Procedure

 

Visit Window (Days)

 

N/A

 

± 5

 

± 14

Informed consent

 

X

 

 

 

 

Review of entrance criteria

 

X

 

 

 

 

Medical history

 

 

 

 

 

 

Physical examination(2)

 

 

 

 

 

 

Recent health status

 

X

 

X

 

 

Vital signs, weight and height measurements(3)

 

X

 

X

 

X

Electrocardiogram

 

X

 

 

 

X

Urinalysis (dipstick) (4)

 

X

 

 

 

X

Chemistry blood collection(5)

 

X

 

 

 

X

Hematology blood collection(5)

 

X

 

 

 

X

Coagulation blood collection(5)

 

X

 

 

 

X

PTH(1-84)

 

 

 

 

 

X

25-hydroxy vitamin D level

 

 

 

 

 

X

1,25-dihydroxy vitamin D level

 

 

 

 

 

X

Serum markers of bone metabolism (6)

 

X

 

 

 

X

BA058 antibody levels

 

 

 

 

 

X

24-hour urine collection (for calcium:creatinine and creatinine clearance)(7)

 

X

 

 

 

X

Clinical and radiologic (spine, lumbar and thoracic vertebrae) fracture
assessments

 

 

 

 

 

X

Bone mineral density of hip and spine by DXA(8)

 

 

 

 

 

X

Bone mineral density of wrist by DXA(9)

 

 

 

 

 

X

Calcium and vitamin D supplements

 

<———————Daily———————>

Alendronate administration (if applicable)

 

<———————Daily———————>

Other osteoporosis medication administration (if applicable)

 

<—Dosing as per prescribing information—>

Study medication resupply (if applicable)

 

 

 

X

 

 

Subject diary review(10)

 

 

 

X

 

X

Document adverse events and concomitant medications

 

<———————Daily———————>

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

14.2                  Suggested Schedule of Events and Procedures by Study Visit

 

The purpose of this guide is to provide more detailed instructions for the study
procedures listed in Appendix 14.1.  This guide presents the procedures in a
suggested sequence of performance at each study visit.  Further information may
be found within the protocol and in other study reference manuals (e.g., ECG,
clinical lab sample processing).

 

Of note:

 

·                  Blood and urinalysis samples are to be obtained under fasting
conditions (NPO. for 8 hours; water is acceptable) in the morning of each
scheduled study visit.

 

·                  DXA Scans: Always use the same study-validated machine;
preferably the same technician.

 

·                  The 24-hour urine collection will be started at home the day
before the clinic visit where the collection is required.  Subjects will be
instructed to discard the first morning void and begin the collection at least
24 hours before their clinic visit the following day. They will collect all
urine for 24 hours with a final void before coming to the clinic. Routine
urinalyses are to be performed using samples freshly voided during the clinic
visit.  Subjects should receive a reminder to initiate their 24-hour urine 2
days before their scheduled visit.

 

·                  The osteoporosis medication will be sourced locally. The cost
of alendronate will be reimbursed by the Sponsor.  The Sponsor or the
Investigator will not be responsible for the costs of the alternative medication
should one be prescribed.

 

·                  Subjects will be instructed to take the calcium and vitamin D
supplements daily (in the evening with or without food or as otherwise
instructed by the Investigator) until discharge from the study.  This is
required until the end of Month 6.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Definitions of Common Procedures:

 

The terms used in the by-visit schedule that follows are further defined below.

 

Recent health status (document any changes from last visit)

 

·                  Question subject regarding any new health issues

·                  Question subject regarding any new adverse events

·                  Question subject regarding any new concomitant medications

·                  Question subject regarding any new issues related to ability
to continue with study

 

Pulse, respiration and temperature:

 

·                  Pulse rate (beats/minute) taken after approximately five
minutes in the supine position.

·                  Respiration rate (breaths/minute).

·                  Body temperature (°C).

 

Weight and height measurements:

 

·                  Weight (kg).

·                  Height (cm) standing measurements are to be performed using
the same medical stadiometer and standardized procedures each time.

 

Orthostatic blood pressure:

 

·                  Orthostatic blood pressure (mmHg) (measured in same arm each
time/each visit) is measured after five minutes in the supine position followed
by a measurement taken after 3 minutes in the standing position.

 

ECG

 

·                  Twelve-lead supine electrocardiogram

·                  Print hard copy for reading by qualified study personnel

·                  More than one ECG may be performed per time point.

 

24 hour urine collection

 

·                  Subject to discard first morning void (suggest 6 a.m.) on day
before clinic visit

·                  Subject to collect urine for approximately 24 hours

·                  Subject to collect final void at end of collection and bring
collection to clinic.

·                  Process for calcium and creatinine

 

Urinalysis

 

·                  Obtain under fasting conditions (NPO. except water for 8
hours)

·                  Routine urinalysis is to be performed using a sample freshly
voided during the clinic visit (microscopic examination if positive dipstick).

 

Review study medication administration procedures with subject

 

·                  Alendronate should be taken daily, preferably at the same
time each morning

 

Scheduling and instructions for next clinic visit

 

·                  Schedule visit

·                  Remind subject of any fasting requirements

·                  Provide urine collection instructions and materials as
necessary

·                  Remind subjects to complete the diaries until the end of the
study

 

Vitamin D and calcium supplements

 

·                  Vitamin D and calcium supplements are required throughout the
study.  Only those supplements supplied as part of study medication may be used
and are to be used at the daily recommended dose (see Section 5.1.3).

·                  Supplements should be taken in the evening, with or without
food as instructed by the Investigator.

·                  At each study visit, assess the subject’s supply and resupply
as necessary.

·                  Drug usage reconciliation is to be performed when a new
supply is provided.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Visit 10 for Study BA058-05-003
Day 1 Visit for Study BA058-05-005
Day 1

 

 

 

VISIT

 

ACTIVITIES

Day 1

Day 1
Visit for
Study
BA058-
05-005

 

Visit 10
for Study
BA058-
05-003

 

Written informed consent must be obtained
Recent health status

·                  Document any changes since End-of-Treatment visit (Visit 9)
from Study BA058-05-003

Study staff will receive your prior days 24-hour urine sample
Subject diary review

·                  Review study medication diary (calcium and vitamin
D)/dispense new diary if necessary

·                  Record deviations in dosing or any AEs in source documents
and CRFs

·                  Collect diaries and enter data into CRF

Vital signs
Orthostatic blood pressure
Weight and height
ECG
Blood collection: fasting conditions (NPO except water for 8 hours)

·                  Chemistry

·                  Hematology

·                  Coagulation (PT and PTT)

·                  Serum markers of bone metabolism, where applicable

·                  PINP

·                  bone-specific alkaline phosphatase

·                  serum osteocalcin

·                  serum CTX

·                  Urinalysis (Dipstick)

Study medication

·                  Dispense three month supply of osteoporosis medication

·                  Assess subject’s supply of calcium and vitamin D supplements;
resupply as necessary

·                  Instruct subject to take daily until they are discharged from
the study

Scheduling and instructions for next clinic visit

·                  Remind subject to take study medication as instructed

·                  Remind subject to record study medication use

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Month 3 Visit for Study BA058-05-005
Day 90 (±5 days)

 

 

 

VISIT

 

Activities

Month 3

 

Recent health status

·                  Document any changes since previous visit

Vital signs

Subject diary review

·                  Review study medication diary/dispense new diary if necessary

·                  Record deviations in dosing or any AEs in source documents
and CRFs.

·                  Collect diaries and enter data into CRF

Study medication

·                  Dispense additional three month supply of osteoporosis
medication

·                  Assess subject’s supply of calcium and vitamin D supplements;
resupply as necessary, instruct subject to take daily until they are discharged
from the study

Scheduling and instructions for next clinic visit

·                  24-hour urine collection: Dispense urine collection container
and instruct subjects to perform 24-hour urine collection beginning the morning
24 hours prior to their next scheduled visit (Month 6)

·                  Remind subject to take study medication as instructed

·                  Remind subject to record study medication use

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Month 6 Visit for Study BA058-05-005
Day 180 (±14 Days)

 

 

 

VISIT

 

Activities

Month 6

 

Recent Health Status

·                  Document any changes from last visit

Collect 24 hour urine sample from subject

Study staff will receive your prior days 24-hour urine sample

·                  Review diary of study medication

·                  Collect diary and enter data into CRF, record dosing
deviations or any AEs in source documents and CRFs

Calcium and vitamin D supplements

·                  Collect any leftover supplements

Vital signs, weight and height measurement

Orthostatic blood pressure

ECG

Blood collection: fasting conditions (NPO except water for 8 hours)

·                  Chemistry

·                  Hematology

·                  Coagulation (PT and PTT)

·                  Serum markers of bone metabolism, where applicable

·                  PINP

·                  bone-specific alkaline phosphatase

·                  serum osteocalcin

·                  serum CTX

·                  BA058 antibody levels

·                  Urinalysis (Dipstick)

·                  Collect unused study medication

Clinical and radiologic fracture evaluations

·                  Obtain antero-posterior and lateral radiographs of the lumbar
and thoracic vertebrae

·                  Document any non-vertebral fractures

Bone mineral density

·                  Perform DXA of spine (L1-L4), hip (femoral neck), and wrist
(distal 1/3 radius), where applicable.

Discharge subject from study

·                  Subject is terminated from the study unless abnormal clinical
laboratory tests or adverse events require further follow-up

Discuss continuing treatment options

·                  Following the Extension Study completion, all subjects will
be given the opportunity to receive an additional 18 months of treatment with
alendronate

·                  Subjects will receive standard-of-care management according
to their physician

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

14.3        Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Haematology

 

 

 

 

 

 

 

 

 

 

WBC (x109/L)

 

4

 

3.0 - 3.9

 

2.0 - 2.9

 

1.0 - 1.9

 

< 1.0

Platelets (x109/L)

 

WNL

 

75.0 - normal

 

50.0 - 74.9

 

25.0 - 49.9

 

< 25.0

Haemoglobin (g/L);
(mmol/L)

 

WNL

 

100.0 - normal;
6.2 - normal

 

80.0 - 99.0;
5.0 - 6.1

 

65.0 - 79.0
4.0 - 4.9

 

< 65.0
< 4.0

Granulocytes/ Bands (x109/L)

 

2

 

1.5 - 1.9

 

1.0 - 1.4

 

0.5 - 0.9

 

< 0.5

Lymphocytes (x109/L)

 

2

 

1.5 - 1.9

 

1.0 - 1.4

 

0.5 - 0.9

 

< 0.5

Haemorrhage

 

none

 

mild, no transfusion

 

gross,
1 - 2 units transfusion per episode

 

gross,
3 - 4 units transfusion per episode

 

massive,
> 4 units transfusion per episode

Coagulation

 

 

 

 

 

 

 

 

 

 

Fibrinogen

 

WNL

 

0.99 - 0.75 x N

 

0.74 - 0.50 x N

 

0.49 - 0.25 x N

 

< 0.25 x N

Prothrombin time(quick)

 

WNL

 

1.01 - 1.25 x N

 

1.26 - 1.50 x N

 

1.51 - 2.00 x N

 

> 2.00 x N

Partial thromboplastin time

 

WNL

 

1.01 - 1.66 x N

 

1.67 - 2.33 x N

 

2.34 - 3.00 x N

 

> 3.00 x N

Metabolic

 

 

 

 

 

 

 

 

 

 

Hyperglycaemia (mmol/L)

 

< 6.4

 

6.4 - 8.9

 

9.0 - 13.9

 

14.0 - 27.8

 

> 27.8 or ketoacidosis

Hypoglycaemia (mmol/L)

 

> 3.6

 

3.6 - 3.1

 

3.0 - 2.3

 

2.2 - 1.7

 

< 1.7

Amylase

 

WNL

 

< 1.5 x N

 

1.5 - 2.0 x N

 

2.1 - 5.0 N

 

> 5.0 x N

Hypercalcaemia (mmol/L)

 

< 2.65

 

2.65 - 2.88

 

2.89 - 3.13

 

3.14 - 3.36

 

> 3.37

Hypocalcaemia (mmol/L)

 

> 2.10

 

2.10 - 1.94

 

1.93 - 1.74

 

1.73 - 1.52

 

< 1.51

Hypomagnesaemia (mmol/L)

 

> 0.58

 

0.58 - 0.48

 

0.47 - 0.36

 

0.35 - 0.24

 

< 0.23

Gastrointestinal

 

 

 

 

 

 

 

 

 

 

Nausea

 

none

 

able to eat reasonable intake

 

intake significantly decreased but can eat

 

no significant intake

 

—

Vomiting

 

none

 

1 episode
in 24 hrs

 

2 - 5 episodes
in 24 hrs

 

6 - 10 episodes
in 24 hrs

 

> 10 episodes in 24 hrs or requiring parenteral support

Diarrhoea

 

none

 

increase of 2 - 3 stools/day over pre-Rx

 

increase of 4 - 6 stools/day, or nocturnal stools, or moderate cramping

 

increase of 7 - 9 stools/day, or incontinence, or severe cramping

 

increase of > 10 stools/day or grossly bloody diarrhoea, or need for parenteral
support

Stomatitis

 

none

 

painless ulcers, erythema, or mild soreness

 

painful erythema, oedema, or ulcers but can eat solids

 

painful erythema, oedema, or ulcers and cannot eat solids

 

requires parenteral or enteral support for alimentation

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Liver

 

 

 

 

 

 

 

 

 

 

Bilirubin (N = 17 µmol/L)

 

WNL

 

—

 

< 1.5 x N

 

1.5 - 3.0 x N

 

> 3.0 x N

Transaminase (SGOT, SGPT)

 

WNL

 

2.5 x N

 

2.6 - 5.0 x N

 

5.1 - 20.0 x N

 

> 20.0 x N

Alkaline phosphatase or 5-nucleotidase

 

WNL

 

< 2.5 x N

 

2.6 - 5.0 x N

 

5.1 - 20.0 x N

 

> 20.0 x N

Liver- clinical

 

No change from baseline

 

—

 

—

 

precoma

 

hepatic coma

Kidney, bladder

 

 

 

 

 

 

 

 

 

 

Creatinine

 

WNL

 

< 1.5 x N

 

1.5 - 3.0 x N

 

3.1 - 6.0 x N

 

> 6.0 x N

Proteinuria

 

No change

 

1 (+) or
< 0.3 g% or 3 g/L

 

2 - 3 (+) or
0.3-1.0 g% or 3-10 g/L

 

4 (+) or
> 1.0 g% or > 10g/L

 

nephrotic syndrome

Haematuria

 

Negative

 

microscopic only

 

gross,
no clots no Rx needed

 

gross and clots
bladder irrigation

 

requires transfusion
or cystectomy

Weight gain/ loss

 

< 5.0 %

 

5.0 - 9.9 %

 

10.0 - 19.9 %

 

20.00%

 

—

Pulmonary

 

 

 

 

 

 

 

 

 

 

Pulmonary

 

none or no change

 

asymptomatic, with abnormality in PFTs

 

dyspnoea on significant exertion

 

dyspnoea at normal level of activity

 

dyspnoea at rest

Cardiac

 

 

 

 

 

 

 

 

 

 

Cardiac arrhythmias

 

none

 

asymptomatic, transient, requiring no therapy

 

recurrent or persistent, no therapy required

 

requires treatment

 

requires monitoring; or hypotension, or ventricular tachycardia or fibrillation

Cardiac function

 

none

 

asymptomatic, decline of resting ejection fraction by less than 20 % of baseline
value

 

asymptomatic, decline of resting ejection fraction by more than 20 % of baseline
value

 

mild CHF, responsive to therapy

 

severe or refractory CHF

Cardiac ischaemia

 

none

 

non-specific T- wave flattening

 

asymptomatic, ST and T wave changes suggesting ischaemia

 

angina without evidence of infraction

 

acute myocardial infarction

Cardiac- pericardial

 

none

 

asymptomatic effusion, no intervention required

 

pericarditis (rub, chest pain, ECG changes)

 

symptomatic effusion; drainage required

 

tamponade; drainage urgently required

Hypertension

 

none or no change

 

asymptomatic, transient increase by greater than 20 mmHg (D) or to > 150/100 if
previously WNL.
No treatment required.

 

recurrent or persistent increase by greater than 20 mmHG (D) or to > 150/100 if
previously WNL.
No treatment required.

 

requires therapy

 

hypertensive crisis

Hypotension

 

none or no change

 

changes requiring no therapy (including transient orthostatic hypotension)

 

requires fluid replacement or other therapy but not hospitalisation

 

requires therapy and hospitalisation; resolves within 48 hrs of stopping the
agent

 

requires therapy and hospitalisation for > 48 hrs after stopping the agent

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Neurologic

 

 

 

 

 

 

 

 

 

 

Neuro: sensory

 

none or no change

 

mild paraesthesias;
loss of deep tendon reflexes

 

mild or moderate objective sensory loss moderate paraesthesias

 

severe objective sensory loss or paraesthesias that interfere with function

 

—

Neuro: motor

 

none or no change

 

subjective weakness;
no objective findings

 

mild objective weakness without significant impairment of function

 

objective weakness with impairment of function

 

paralysis

Neuro: cortical

 

none

 

mild somnolence or agitation

 

moderate somnolence or agitation

 

severe somnolence, (>50 % waking hours), agitation, confusion, disorientation or
hallucinations

 

coma, seizures, toxic psychosis

Neuro: cerebellar

 

none

 

slight incoordination, dysdiadochokinesia

 

intention tremor, dysmetria, slurred speech, nystagmus

 

locomotor ataxia

 

cerebellar necrosis

Neuro: mood

 

no change

 

mild anxiety or depression

 

moderate anxiety or depression

 

severe anxiety or depression

 

suicidal ideation

Neuro: headache

 

none

 

mild

 

moderate or severe
but transient

 

unrelenting and severe

 

—

Neuro: constipation

 

none or no change

 

mild

 

moderate

 

severe

 

ileus > 96 hrs

Neuro: hearing

 

none or no change

 

asymptomatic, hearing loss on audiometry only

 

tinnitus

 

hearing loss interfering with function but correctable with hearing aid

 

deafness not correctable

Neuro: vision

 

none or no change

 

—

 

—

 

symptomatic subtotal loss of vision

 

blindness

Pain

 

 

 

 

 

 

 

 

 

 

Pain

 

none

 

mild

 

moderate

 

severe

 

reg. narcotics

Skin

 

 

 

 

 

 

 

 

 

 

Skin

 

none or no change

 

scattered macular or papular eruption or erythema that is asymptomatic

 

scattered macular or papular eruption or erythema with pruritus or other
associated symptoms

 

generalised symptomatic macular, papular or vesicular eruption

 

exfoliative dermatitis or ulcerating dermatitis

Alopecia

 

 

 

 

 

 

 

 

 

 

Alopecia

 

no loss

 

mild hair loss

 

pronounced or total hair loss

 

—

 

—

Allergy

 

 

 

 

 

 

 

 

 

 

Allergy

 

none

 

transient rash,
drug fever < 38oC (<100.4oF)

 

urticaria,
drug fever 38oC (100.4oF),
mild bronchospasm

 

serum sickness, bronchospasm requiring parenteral medication

 

anaphylaxis

Local

 

 

 

 

 

 

 

 

 

 

Local

 

none

 

pain

 

pain and swelling with inflammation or phlebitis

 

ulceration

 

plastic surgery indicated

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Fever of unknown origin

 

 

 

 

 

 

 

 

 

 

Fever of unknown origin

 

none

 

37.1 - 38.0o C
98.7o - 100.4o F

 

38.1 - 40.0o C
100.5 - 104o F

 

> 40.0oC (> 104o F) for less than 24hrs

 

> 40.0o C (> 104o F) for more than 24 hrs or accompanied by hypotension

Infection

 

 

 

 

 

 

 

 

 

 

Infection

 

none

 

mild

 

moderate

 

severe

 

life-threatening

Additional events

 

 

 

 

 

 

 

 

 

 

Asthenia

 

analogous to Karnofsky index (WHO grading)

 

 

 

 

 

 

 

 

Chills

 

analogous to fever

 

 

 

 

 

 

 

 

Peripheral oedema

 

analogous to weight gain

 

 

 

 

 

 

 

 

Anorexia

 

analogous to weight loss

 

 

 

 

 

 

 

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

Attachment F

Reports and Information Management/Regular Meetings

 

The Project Committee for Work Statement NB-3 shall be composed of the following
members from Radius and the following members from NB:

 

Radius Members:  (1) Nicholas Harvey, (2) Louis Brenner and (3) Michael Wyzga.

 

NB Members:  (1) Bente Juel Riis and (2) Claus Christiansen.

 

The Committee will meet on the telephone when needed and in person when
appropriate.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

Attachment G

Special Insurance

 

Radius will maintain insurance with respect to the following jurisdictions
during the conduct of the clinical study that is the subject of Work Statement
NB-3.

 

 

 

 

 

 

 

 

 

 

 

Primary

 

 

 

Trial

 

 

 

Local Policy

 

Local Policy

 

Policy Limit

 

Country

 

Phase

 

Policy Period

 

Limit

 

Sublimit

 

(Aggregate)

 

 

[g17732le19i001.jpg]

 

MASTER US POLICY

 

 

 

January 30, 2013 - January 30, 2014

 

$

10,000,000

 

N/A

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i002.jpg]

 

DENMARK

 

III

 

August 9, 2012 - August 9, 2014

 

€

5,000,000

 

NONE

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i003.jpg]

 

CZECH REPUBLIC

 

III

 

September 30, 2012 - March 31, 2015

 

€

2,500,000

 

€

250,000

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i004.jpg]

 

ESTONIA

 

III

 

August 9, 2012 - August 9, 2014

 

€

5,000,000

 

NONE

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i005.jpg]

 

LITHUANIA

 

III

 

September 30, 2012 - March 31, 2015

 

11,700,000 LTL

 

100,000 LTL

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i006.jpg]

 

POLAND

 

III

 

August 9, 2012 - August 9, 2014

 

€

5,000,000

 

NONE

 

$

10,000,000

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

 

 

 

 

 

 

 

 

 

 

Primary

 

 

 

Trial

 

 

 

Local Policy

 

Local Policy

 

Policy Limit

 

Country

 

Phase

 

Policy Period

 

Limit

 

Sublimit

 

(Aggregate)

 

 

[g17732le19i007.jpg]

 

ROMANIA

 

III

 

September 30, 2012 - March 31, 2015

 

€

5,000,000

 

NONE

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i008.jpg]

 

BRAZIL

 

III

 

September 30, 2012 - March 31, 2015

 

$

500,000

 

NONE

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i009.jpg]

 

HONG KONG

 

III

 

August 9, 2012 - August 9, 2014

 

20,000,000 HKD

 

10,000,000 HKD

 

$

10,000,000

 

 

 

 

 

 

 

 

 

 

 

 

 

 

[g17732le19i010.jpg]

 

ARGENTINA

 

III

 

September 30, 2012 - March 31, 2015

 

$

1,000,000

 

$

100,000

 

$

10,000,000

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Work Statement NB-3

Attachment H

Transfer of Obligation

 

See Work Statement NB-3 Attachment C.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Attachment I

Form of Enterprise CTA

CLINICAL TRIAL AGREEMENT WITH INVESTIGATOR

 

Protocol No. BA058-05-005

 

This Clinical Trial Agreement (“Agreement”) is entered into by and among CENTER
FOR CLINICAL AND BASIC RESEARCH A/S, Telegrafvej 4, 1, 2750 Ballerup, Denmark
(“CCBR”) on behalf of itself and its ten [affiliated][controlled] Clinical Study
Sites listed below and Nordic Bioscience A/S, Herlev Hovedgade 207, 2730 Herlev,
Denmark (“Nordic Bioscience”), representing the interests of Radius Health, Inc.
(“Sponsor”) concerning:

 

Study Protocol BA058-05-005: An Extension Study to Evaluate Six Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-003, which will guide the
performance of the Study, has been prepared by Radius and Nordic Bioscience and
accepted by the Clinical Study Sites.

 

CCBR has the legal authority to bind the following clinical study sites (the
“Clinical Study Site(s)”):

 

1.              CCBR-Ballerup, Ballerup Byvej 222, DK 2750 Ballerup, Denmark

2.              CCBR-Ålborg, Hobrovej 42D, DK-9000 Ålborg, Denmark

3.              CCBR-Vejle, Orla Lehmannsgade 1, DK-7100 Vejle

4.              CCBR-Tallinn, Pärna 4, 10128 Tallinn, Estonia

5.              CCBR-Vilnius, Smélio 20, Vilnius, Lithuania

6.              CCBR-Bucharest, 2-4 Aleea Buchetului, sector 3, bl. C2,
Bucharest, Romania

7.              CCBR-Rio de Janeiro, Rua Meno Barreto, Botafogo, Rio de Janeiro,
Brazil

8.              CCBR-Sao Paolo, Avenida Indianópolis nº 1005, Moema. São Paulo -
SP - ZIP CODE: 04063-002

9.              CCBR-Pardubuce, Masarykovo náměstí 2667, 530 02 Pardubice, Czech
Republic

10.       CCBR-Brno, Hybešova 18, 60200 Brno, Czech Republic

11.       CCBR-Prague, Vinohradská 1597/174 Praha 3 — Vinohrady 130 00 Czech
Republic

12.       CCBR-Warsaw, Al. Dzieci Polskich PL04-730 Warsaw

13.       CCBR-Lodz, Al Pilsudskiego 9 90-368 Lodz Poland

14.       CCBR Hong Kong, Center for Health and Medical Research, Hong Kong, 6
Floor, Tower II, New World Tower, 18 Queen’s Road Central, Hong Kong

15.       CCBR-Buenos Aires, Fitz Roy 2468 1st floor Buenos Aires, Argentina

 

WHEREAS, the Clinical Study Sites each employ a Principal Investigator and are
willing to conduct a clinical trial (the “Study”), in accordance with the
above-referenced Protocol and Nordic Bioscience requests each Clinical Study
Site to undertake such Study;

 

NOW THEREFORE, the parties agree as follows:

 

1.                    SCOPE OF WORK

 

Nordic Bioscience hereby appoints each of the Clinical Study Sites to conduct
the Study, and each of the Clinical Study Sites, each having a Principal
Investigator who is an employee of such Clinical Study Site, undertakes that
such Clinical Study Site’s employees, agents, and staff shall carry out the
Study in a professional, competent manner in accordance with the terms of the
Protocol and this Agreement. Each of the Clinical Study Sites hereby confirms
that it has enough time and resources to perform the Study according to the
highest quality standards.

 

The Principal Investigators shall each review all case report forms (“CRFs”) for
Study subjects enrolled at the applicable Clinical Study Site to ensure their
accuracy and completeness, shall review and understand the information in the
investigator’s brochure, shall ensure that all informed consent requirements are
met, and shall ensure that all required reviews and approvals (or favorable
opinions) by applicable regulatory authorities and Independent Ethics Committees
(“ECs”) are obtained. The Clinical Study Sites and the Principal Investigators
shall each ensure that all clinical data are accurate, complete, and legible.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

2.                    PERFORMANCE PERIOD AND ENROLLMENT OF STUDY SUBJECTS

 

The Study will commence upon execution of this Agreement and will continue until
completion of the Study as required by the Protocol (including any amendments
thereto), unless this Agreement is terminated earlier pursuant to Section 14
hereof.

 

The Study will involve the enrollment and completion of a maximum of Two Hundred
Forty (240) evaluable study subjects meeting all Protocol eligibility
requirements and protocol procedures (the “Study subjects”). Nordic Bioscience
shall not be obligated to pay any sums for tests performed on Study subjects who
do not meet all Protocol eligibility criteria or for additional study subjects
who are enrolled in the Study without Nordic Bioscience’s prior written
approval.

 

Nordic Bioscience will close study subject enrollment into the Study when the
Protocol-specified target number of study subjects have been enrolled at all
Clinical Study Sites. Therefore, study subject enrollment into the Study may be
closed before a specified number of study subjects have been enrolled at any
particular Clinical Study Site.

 

Nordic Bioscience will provide financial support for the Study conducted at the
Clinical Study Sites according to the terms specified in Schedule A.

 

3.                    DATA

 

Sponsor shall own all data and work product relating to the Study, including all
CRF’s, data, documentation, information, materials and results in whatever form
generated during the conduct of the Study. Each of the Clinical Study Sites
and/or the Principal Investigators shall ascertain that it may store data in a
computerized form and also that it is entitled to transfer all such computerized
data to Nordic Bioscience. Each of the Clinical Study Sites may use the data and
work product it generates under this Agreement solely for purposes of performing
the Study in accordance with the terms of this Agreement.  Each of the Clinical
Study Sites and/or the Principal Investigators shall promptly and fully produce
all data, records and information relating to the Study to Nordic Bioscience and
the Sponsor and their representatives during normal business hours, and shall
assist them in promptly resolving any questions and in performing audits or
reviews of original subject records, reports, or data sources. Each of the
Clinical Study Site agrees to cooperate with the representatives of Nordic
Bioscience and Sponsor who visit the Clinical Study Site.

 

4.                    COST AND PAYMENT

 

Cost and payment terms are set forth in Schedule A attached to this Agreement
and incorporated herein by reference. Each of the Clinical Study Sites agrees to
provide Nordic Bioscience with all requests for payment under the terms set
forth in Schedule A within six (6) months of Study completion by Clinical Study
Sites under the terms of this Agreement. Nordic Bioscience shall not be
obligated to make any payments to Clinical Study Sites after this six (6) month
period has expired.  Study completion is defined herein as Nordic Bioscience has
received all data and no further follow up is necessary with the Clinical Study
Sites.

 

5.                    CONFIDENTIAL INFORMATION

 

During the term of this Agreement and for a period of five (5) years after
completion of the Study, the Clinical Study Sites and the Principal
Investigators shall not disclose or use for any purpose other than performance
of the Study, all information (including but not limited to the terms of this
Agreement, the Protocol, CRF’s, and any secrets, know-how, privileged records or
other confidential or proprietary information and data disclosed to the Clinical
Study Sites), and materials (including, but not limited to, the Study Drug and
comparator products), provided to the Clinical Study Site by Nordic Bioscience,
Sponsor, or their agents, and all data, reports and information, relating to the
Study or its progress developed by the Clinical Study Sites and/or the Principal
Investigator under this Agreement (the “Confidential Information”). Sponsor
shall own the Confidential Information.  The Clinical Study Sites and the
Principal Investigators shall keep the Confidential Information strictly
confidential and shall disclose it only to those personnel involved in
conducting the Study on a need-to-know basis. These confidentiality obligations
shall not apply to Confidential Information to the extent that it: (a) is or
becomes publicly available through no fault of the Clinical Study Site; (b) is
disclosed to the Clinical Study Site by a third party not subject to any
obligation of confidence; (c) must be disclosed to ECs, or applicable regulatory
authorities; (d) must be included in any subject’s informed consent form; (e) is
published in accordance with Section 6; or (f) is required to be disclosed by
applicable law.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

6.                    PUBLICATIONS

 

6.1.                            Any and all results of the Study shall be the
sole property of Sponsor.  Sponsor will have the right to use the results of the
Study in any manner deemed appropriate to Sponsor’s business interest and
Sponsor and Nordic Bioscience will each have the right to report the names of
the Clinical Study Sites as required by law or governmental regulation. Neither
Sponsor nor any party to this Agreement, however, will use another party’s (or
Sponsor’s) name in advertising, promotions, or other commercial material without
the other party’s (or Sponsor’s) express written permission, except that Nordic
Bioscience and Sponsor may quote from and/or reference any publications
resulting from the Study authored by, or reviewed and approved by the Clinical
Study Sites.

 

6.2.                            It is the intention to publish the Study results
in scientific journals.  Any publication of Study results or data shall be made
in accordance with the provisions of Section 11.2 of the Protocol.

 

7.                    LICENSE

 

7.1.                            Each Clinical Study Site and Principal
Investigator acknowledges that Sponsor owns all proprietary and intellectual
property rights in the Study Drug and the related materials being provided to
the Principal Investigator and the Clinical Study Site pursuant to this
Agreement, including but not limited to the Protocol and the CRF’s produced in
the performance of the Study (collectively, “Sponsor Technology”).  Each
Clinical Study Site and Principal Investigator agrees to take no action
inconsistent with Sponsor’s ownership of such proprietary and intellectual
property rights.  It is agreed that neither Nordic Bioscience (including
Sponsor) nor the Clinical Study Sites transfers to the other by operation of
this Agreement any patent right, copyright right, or other proprietary right of
either party, except as contemplated by Section 7.2.  Each Clinical Study Site
and Principal Investigator agrees to disclose promptly and fully to Nordic
Bioscience all creative ideas, developments, discoveries, methodologies,
improvements and inventions, whether or not patentable, arising as a direct
result of the work performed under the Study. The Sponsor, acting through Nordic
Bioscience, hereby grants each of the Clinical Study Sites a nonexclusive,
non-transferable, royalty-free license to use the Study Drug and Sponsor
Technology at the Clinical Study Site solely for purposes of conducting the
Study.  Neither the Clinical Study Site nor the Principal Investigator will use
or permit use of Study Drug or Sponsor Technology by any third party for any
purpose other than the completion of the Study without Sponsor’s prior written
permission

 

7.2.                            If a Clinical Study Site, as a direct
consequence of the work on the Clinical Study, conceives or reduces to practice
any new invention, then: (i) if such invention is conceived or reduced to
practice solely by the Clinical Study Site, it shall be owned by the Clinical
Study Site and (ii) if such invention is conceived or reduced to practice by the
Clinical Study Site and Sponsor or Clinical Study Site and Nordic Bioscience, it
shall be jointly owned by the Clinical Study Site and Sponsor or Clinical Study
Site and Nordic Bioscience.  All of the Clinical Study Site’s rights to any new
invention related to a new use for the Study Drug will be licensed to Sponsor,
upon its request and on commercially reasonable terms.  For new inventions which
are not related to a new use for the Study Drug, Clinical Study Site grants
Sponsor a first option to obtain an exclusive license to any invention owned in
whole or in part by the Clinical Study Site, which shall be negotiated by the
parties and contain commercially reasonable terms.  Such option shall be
exercisable for a period of six (6) months from the date the Clinical Study Site
discloses the invention to Sponsor. . Clinical Study Sites will fully cooperate
with Nordic Bioscience in obtaining whatever patent protection may be available
on inventions, ideas, and developments arising from their work on the Study, and
will further cooperate with Nordic Bioscience in executing all documents deemed
necessary by Nordic Bioscience or Sponsor for purposes of procuring such patent
protection.

 

7.3.                            Each Clinical Study Site hereby represents and
warrants to Nordic Bioscience that all personnel affiliated with the Clinical
Study Site and participating in the Study, including the applicable Principal
Investigator, are subject to written agreements requiring them to disclose and
assign any new invention to the Clinical Study Site.

 

8.                    USE OF NAME (ADVERTISING)

 

The Clinical Study Sites and/or Principal Investigators shall obtain prior
written consent from Nordic Bioscience before using the name, symbols or marks
of Nordic Bioscience or Sponsor in any form of publicity in connection with the
Study.  If any of the Clinical Study Sites or Nordic Bioscience is legally
required to make any disclosure

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

that identifies the existence or terms of the Agreement, then either may do so
without prior written consent from the other but the applicable Clinical Study
Site(s) must notify Nordic Bioscience within five (5) business days of such
disclosure.

 

9.                    CHANGES TO THE PROTOCOL

 

9.1.                            Subject to Section 9.2, any changes to the
Protocol may be made only with the prior agreement of the Sponsor. If these
changes will affect the cost of the Study, Nordic Bioscience shall provide the
Clinical Study Sites with a written estimate of such change in Study cost.

 

9.2.                            If generally accepted standards of Good Clinical
Practice relating to the safety of study subjects require a deviation from the
Protocol, these standards will be followed. Any party who becomes aware of the
need for a deviation from the Protocol will immediately notify the other parties
to this Agreement and the Sponsor of the facts causing the deviation as soon as,
the facts are known to that party but no such deviation or change shall be
implemented without the prior written approval of Nordic Bioscience and Sponsor;
Nordic Bioscience and Sponsor shall promptly confer and provide a prompt written
response regarding any deviation proposed pursuant to this Section 9.2.

 

9.3.                            Clinical Study Site shall coordinate, and shall
cause each Principal Investigator to coordinate, with the relevant institutional
review board or ethics committee (the “EC”) to obtain the EC’s written approval
of such Principal Investigator’s conduct of the Study at Clinical Study Site,
including approval of the Protocol and informed consent form to be executed by
all subjects enrolled by Principal Investigator in the Study (the “Informed
Consent Form”).  Clinical Study Site shall be responsible for providing Sponsor
with a copy of each such approval, together with information about the members
of the EC and all relevant correspondence with the EC. In addition, Clinical
Study Site shall coordinate, and shall cause Principal Investigator to
coordinate, with the EC to obtain review and approval in writing of any
amendments made to a Protocol by the parties.  In the event the EC requires
changes in the Protocol or Informed Consent Form, such changes shall not be
implemented until Sponsor and Nordic Bioscience are notified and Sponsor gives
its written approval.  In the event that the EC alters or withdraws its’
approval in any manner, Clinical Study Site shall promptly notify Sponsor and
Nordic Bioscience.  The Protocol and the Informed Consent Form shall not be
revised without the prior written agreement of Sponsor, Nordic Bioscience and
the EC.  Clinical Study Site will use reasonable efforts to ensure that members
of the EC agree to abide by the same obligations of confidentiality as apply to
Clinical Study Site under this Agreement.

 

10.            MATERIALS

 

10.1.                     Sponsor will provide the Study Drug. The Clinical
Study Sites will provide Materials derived from study subjects enrolled in the
study to Nordic Bioscience. The term “Materials” shall include reagents and
materials derived from study subjects enrolled in the Study, including blood,
sera, and other biological materials. The Clinical Study Site shall use the
Study Drug, and any comparator products provided in connection with the Study,
solely for the purpose of properly completing the Study and shall maintain all
Study Drug and any comparator products in a locked, secured area at all times.
Only those persons who are under the Principal Investigator’s, or Principal
Investigators’ direct control and who will be using the Study Drug (and any
comparator products) or Materials for the Study shall have access to the Study
Drug (and any comparator products) or Materials. Upon termination or completion
of the Study, all unused Study Drug and comparator products and all Materials
shall be returned to Nordic Bioscience or at Nordic Bioscience’s sole option,
destroyed.

 

11.             CONFORMANCE WITH LAW AND ACCEPTED PRACTICE

 

11.1.                     The Clinical Study Sites and Principal Investigators
shall perform the Study in strict accordance with the protocol, and any
subsequent amendments thereto, applicable federal, state, and local laws,
regulations and guidelines, good clinical practices (“GCP”), and instructions
provided by Nordic Bioscience.  The Clinical Study Sites and Principal
Investigators shall permit Nordic Bioscience and agencies such as the FDA to
inspect Study records including the Subjects’ medical records. The subject
informed consent form signed by the Subjects shall provide for access to the
Subjects’ medical records by Nordic Bioscience and by agencies such as the FDA.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

 

11.2.                     The Principal Investigator will direct and supervise
the Study in accordance with Section 1. Nordic Bioscience and Sponsor shall have
the right to (a) monitor and audit the activities of the Principal Investigator
and Principal Investigators in the conduct of the Study, and (b) monitor and
audit the collection of data from the Study.

 

11.3.                     The Clinical Study Sites and Principal Investigators
shall retain all records from the Study for the time required by applicable
regulations and at the sole expense of Clinical Study Sites and/or the Principal
Investigator, and to allow for direct access by the applicable government
agencies and representatives of Nordic Bioscience of these records, including
the study subjects’ medical records.

 

11.4.                     Each of the Clinical Study Sites and Principal
Investigators hereby represent and warrant that neither the Clinical Study
Sites, the Principal Investigators nor any of the Clinical Study Sites’ agents
or employees rendering services in connection with the Study is presently: 
(1) the subject of a debarment action or is debarred pursuant to the Generic
Drug Enforcement Act of 1992; (2) the subject of a disqualification proceeding
or is disqualified as a clinical investigator pursuant to 21 C.F.R. § 312.70; or
(3) the subject of an exclusion proceeding or excluded from participation in any
federal health care program under 42 C.F.R. Part 1001 et seq.  Clinical Study
Sites shall notify Nordic Bioscience immediately upon any inquiry concerning, or
the commencement of any such proceeding concerning Clinical Study Sites,
Principal Investigators or any such agent or employee.

 

12.             INDEMNIFICATION

 

12.1.                     Pursuant to a separate indemnity letter in the form of
Exhibit B, the Sponsor shall provide indemnification to the Clinical Study
Sites, the Principal Investigators and any agents and employees of the Clinical
Study Sites from any liabilities, claims, actions or suits for personal injury
or death directly arising out of the administration or use of the Study Drug
during the Study.

 

12.2.                     The Clinical Study Sites and Principal Investigators
shall defend, indemnify and hold harmless Nordic Bioscience, Sponsor and any
agents and employees of Nordic Bioscience and Sponsor from any liabilities,
claims, actions or suits for personal injury or death directly arising from the
negligence or willful misconduct of the Clinical Study Sites, Principal
Investigators or their representatives.

 

13.             STUDY SUBJECT INJURY

 

If a study subject experiences an adverse reaction to the Study Drug, Sponsor
shall provide reimbursement for reasonable and necessary medical expenses
incurred by the study subject for the treatment of these adverse reactions
pursuant to the separate indemnity letter in the form of Exhibit B.  Neither
Nordic Bioscience nor Sponsor will be responsible for any adverse reactions,
which are the result of the negligence or misconduct of the Clinical Study
Sites, Principal Investigators or any of their representatives.

 

14.             TERM; TERMINATION

 

14.1.                     This Agreement shall commence on the date of signature
of this Agreement and shall continue until delivery of the final validated Case
Report Forms. The completion date is dependent on the delivery to the Clinical
Study Sites by Nordic Bioscience of all supplies to be provided by Nordic
Bioscience and necessary to the conduct of the Study. Any delay due to the
failure of supply by Nordic Bioscience, shall be added to the term of the Study.
Clinical Study Sites shall have the right to extend the Agreement should there
be any delay due to the failure of the supply by Nordic Bioscience.

 

14.2.                     This Agreement may be terminated:

 

14.2.1.                by a Clinical Study Site upon thirty (30) days’ prior
written notice only for serious causes resulting in the material breach by
Nordic Bioscience of its obligations to such Clinical Trial Site and only if not
cured in a timely manner using reasonable commercial efforts;

 

14.2.2.                by Nordic Bioscience immediately upon written notice;

 

14.2.3.                by either a Clinical Study Sites or Nordic Bioscience
immediately if the applicable Principal Investigator is unable to continue to
serve and a successor acceptable to both the Clinical Study Site and Nordic
Bioscience is not available; or

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

14.2.4.                upon the occurrence of an event qualifying as a
termination event as described in the Protocol.

 

14.3.                     Upon the effective date of termination, the applicable
Clinical Study Site(s) shall conduct an accounting, which is subject to
verification by Nordic Bioscience.  Within thirty (30) days after Nordic
Bioscience’s receipt of adequate documentation, Nordic Bioscience will make
payment to the applicable Clinical Study Site(s) unless Nordic Bioscience
objects to any charge, in which case, the parties shall use best efforts to
resolve expeditiously any disagreement.  The payments made by Nordic Bioscience
subject to this Section 14.3, will be for:

 

14.3.1.                all services properly rendered and monies properly
expended by the Clinical Study Site  prior to the date of termination and not
yet paid for; and

 

14.3.2.                any reasonable non-cancelable obligations properly
incurred for the Study by the Clinical Study Site prior to the effective date of
termination.

 

14.3.3.                The Clinical Study Site shall credit or return to Nordic
Bioscience any funds not expended by the Clinical Study Site for the Study prior
to the effective termination date.

 

14.4.                     Immediately upon receipt of a notice of termination,
the Principal Investigator shall stop enrolling study subjects into the Study
and shall cease conducting procedures on study subjects already enrolled in the
Study as directed by Nordic Bioscience, to the extent medically permissible and
appropriate.

 

14.5.                     Termination of this Agreement by Nordic Bioscience or
the Clinical Study Sites shall not affect the rights and obligations of the
parties accrued prior to the effective date of the termination. The rights and
duties under Sections 3, 5, 6, 7, 8, 10, 11, 12, 14, 15, 17 and 18 of this
Agreement survive the termination of this Agreement.

 

14.6.                     If this Agreement is terminated prior to completion of
the Study, the Clinical Study Sites shall furnish Nordic Bioscience an
acceptable investigator’s report for the Study.

 

15.             MISCELLANEOUS

 

This Agreement and the Protocol may only be amended by the mutual written
consent of the parties to this Agreement. This Agreement represents the entire
understanding of the parties with respect to the subject matter of this
Agreement. In the event of any inconsistency between this Agreement and the
Protocol, the terms of this Agreement shall govern. The invalidity or
unenforceability of any term or provision of this Agreement shall not affect the
validity or enforceability of any other term or provision of this Agreement. No
waiver of any term, provision or condition of this Agreement in any instance
shall be considered to be a continuing waiver of the same term, provision or
condition, or of any other term, provision or condition of this Agreement.  This
Agreement may be executed in any number of counterparts, each of which shall be
an original and all of which together shall be one document binding on all the
parties even though each of the parties may have signed different counterparts.
This Agreement shall also be considered executed by the parties upon receipt by
Nordic Bioscience by facsimile transmission of the counterparts signed by all
the parties.  This Agreement shall be interpreted under the laws of the state or
province and country in which the applicable Clinical Study Site conducts the
Study.

 

15A.  ASSIGNMENT

 

Neither CCBR nor a Clinical Study Site nor a Principal Investigator may assign
or transfer any rights or obligations under this Agreement without the written
consent of Nordic Bioscience.  Upon Nordic Bioscience’s or Sponsor’s request,
CCBR may assign this Agreement to Nordic Bioscience or to Sponsor or to a third
party, and thereafter CCBR shall not have any obligations or liabilities under
this Agreement, and CCBR shall obtain from each Clinical Study Site such
Clinical Study Site’s prior consent to such an assignment.  Each affected
Clinical Study Site will be given prompt notice of such assignment by the
assignee.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

16.             ACKNOWLEDGEMENT OF PRINCIPAL INVESTIGATORS

 

CCBR shall obtain an executed Acknowledgement of Obligations from each Clinical
Investigator, including each Principal Investigator, participating in the Study
under this Agreement, in the form of Exhibit A hereto, prior to the date that
any such Clinical Investigator shall commence performing services for the
Study.  “Clinical Investigator” means a listed or identified investigator or
subinvestigator for the Study who is directly involved in the treatment or
evaluation of research subjects and such investigator’s spouse and each
dependent child of such investigator.

 

17.             FINANCIAL DISCLOSURE

 

The Clinical Study Sites agrees that, for each listed or identified Clinical
Investigator who is directly involved in the treatment or evaluation of research
subjects, shall return to Nordic Bioscience a financial disclosure form that has
been completed and signed by such Clinical Investigator, which shall disclose
any applicable interests held by those investigators or subinvestigators or
their spouses or dependent children. The Clinical Study Sites shall ensure that
all such forms are promptly updated as needed to maintain their accuracy and
completeness during the Study and for one year after its completion. The
Clinical Study Sites agrees that the completed forms may be subject to review by
governmental or regulatory agencies, Nordic Bioscience and their agents, and the
Clinical Study Sites consents to such review. The Clinical Study Sites further
consents to the transfer of its financial disclosure data to Nordic Bioscience
country of origin, and to the United States of America (“U.S.”) if the Clinical
Study Sites is outside of the U.S., even though data protection may not exist or
be as developed in those countries as in the Clinical Study Site’s own country.

 

18.             ELECTRONIC RECORDS

 

If the data produced by the Clinical Study Sites will be used in support of an
application to the United States Food and Drug Administration (“FDA”) and if the
Clinical Study Sites  uses electronic systems for creating, modifying,
maintaining, archiving, retrieving or transmitting any records that are required
by, or subject to inspection by, the FDA, including, but not limited to, CRFs,
medical records, informed consent forms, test results, or other source
documents, then the Clinical Study Sites  warrants that its systems for such
electronic records are in compliance with Section 21 of the United States Code
of Federal Regulations, Part 11. The Clinical Study Sites further warrants that,
in order to comply with Part 11, it will not use any electronic signatures on
any documents required by, submitted to, or supporting a submission to the FDA
unless it has certified to the FDA that it intends such electronic signatures to
be the legally binding equivalent of a hand-written signature.

 

19.  SPONSOR AS THIRD PARTY BENEFICIARY OF CERTAIN PROVISIONS

 

It is understood and agreed that Sponsor is a third party beneficiary of
Sections 3, 5, 6, 7, 11 and 12 of this Agreement

 

IN WITNESS WHEREOF, the parties hereto have caused their duly authorized
representatives to execute this Agreement as of the date first above.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

CENTER FOR CLINICAL AND BASIC RESEARCH A/S, on behalf of itself and each of the
Clinical Study Sites

Bente Riis, MD, CEO

 

Hans Chr. Hoeck , MD, CEO

 

 

 

 

 

 

Signature

 

 

Signature

 

 

 

 

 

 

Date:

 

 

Date:

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

EXHIBIT A

 

PRINCIPAL INVESTIGATOR’sINVESTIGATOR’S ACKNOWLEDGEMENT OF OBLIGATIONS

 

The undersigned Clinical Investigator acknowledges and agrees that I and Center
for Clinical and Basic Research, Denmark have entered into a Clinical Trial
Agreement with Nordic Bioscience A/S representing the interests of Radius
Health, Inc.  to perform the clinical study under Protocol No. BA058-05-005:

 

An Extension Study to Evaluate Six Months of Standard-of-Care Osteoporosis
Management Following Completion of 18 Months of BA058 or Placebo Treatment in
Protocol BA058-05-003.

 

I agree that Center for Clinical and Basic Research, Denmark was authorized to
enter into the Agreement on my behalf.

 

My payment for my involvement in the trial will not in any way be dependant of
the outcome of the trial. I will not be paid bonuses or the like in case of
positive or negative results. I (including for purposes of this paragraph my
spouse and my dependent children, in each case to the extent applicable) do not
own nor shall I become entitled to own any of the Radius Health, Inc. securities
that are subject to the certain Stock Issuance Agreement entered into between
Radius Health, Inc. and Nordic Bioscience A/S or to otherwise receive any
compensation or other benefit from such Radius Health, Inc. securities or the
proceeds of such Radius Health, Inc. securities.

 

I will, prior to shipment of clinical supplies to my Clinical Study Site provide
Nordic Bioscience with all original documentation necessary for submission to
regulatory authorities, including the U.S. Food & Drug Administration, including
a completed and signed FDA Form 3455 and Form 1572.

 

I agree to comply with all the terms and conditions set forth in the Protocol
and in the Agreement and to be responsible for assuring that any investigators
and study staff under their direct supervision performing work for the Study
contemplated by the Agreement and the Protocol similarly comply with the terms
and conditions contained therein.

 

NAME AND ADDRESS OF PI

 

 

 

 

 

Date:

 

 

 

 

 

 

 

 

Sign:

 

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Attachment K

Indemnity Letter Template

 

[RADIUS HEALTH, INC. LETTERHEAD]

 

[Name of Clinical Study Site]

[Address]

[City, State, Country]

 

1.                   CCBR-Ballerup, Ballerup Byvej 222, DK 2750 Ballerup,
Denmark

2.                   CCBR-Ålborg, Hobrovej 42D, DK-9000 Ålborg, Denmark

3.                   CCBR-Vejle, Orla Lehmannsgade 1, DK-7100 Vejle

4.                   CCBR-Tallinn, Pärna 4, 10128 Tallinn, Estonia

5.                   CCBR-Vilnius, Smélio 20, Vilnius, Lithuania

6.                   CCBR-Bucharest, 2-4 Aleea Buchetului, sector 3, bl. C2,
Bucharest, Romania

7.                   CCBR-Rio de Janeiro, Rua Meno Barreto, Botafogo, Rio de
Janeiro, Brazil

8.                   CCBR-Sao Paolo, Avenida Indianópolis nº 1005, Moema. São
Paulo - SP - ZIP CODE: 04063-002

9.                   CCBR-Pardubuce, Masarykovo náměstí 2667, 530 02 Pardubice,
Czech Republic

10.            CCBR-Brno, Hybešova 18, 60200 Brno, Czech Republic

11.            CCBR-Prague, Vinohradská 1597/174 Praha 3 — Vinohrady 130 00
Czech Republic

12.            CCBR-Warsaw, Al. Dzieci Polskich PL04-730 Warsaw

13.            CCBR-Lodz, Al Pilsudskiego 9 90-368 Lodz Poland

14.            CCBR Hong Kong, Center for Health and Medical Research, Hong
Kong, 6 Floor, Tower II, New World Tower, 18 Queen’s Road Central, Hong Kong

15.            CCBR-Buenos Aires, Fitz Roy 2468 1st floor Buenos Aires,
Argentina

16.            Other sites to be added as relevant

 

Re:  Clinical Trial No. BA058-05-005 (the “Study”) Risk Allocation

 

Dear Ladies and Gentlemen:

 

This letter is delivered to you pursuant to Section 13 of the certain Clinical
Trial Agreement dated                  , 2012 among Center for Clinical and
Basic Research A/S (“CCBR”) on behalf of itself and its affiliates
CCBR-Ballerup, CCBR-Ålborg, CCBR-Vejle, CCBR-Tallinn, CCBR-Warsaw, CCBR Lodz 
and CCBR Hong Kong and Nordic Bioscience (“Nordic Bioscience”), representing the
interests of Radius Health, Inc. (“Radius”) (the “Agreement”).  Capitalized
terms used in this letter and not defined in this letter are used with the
Agreement.  The Agreement concerns the performance of the Study in accordance
with Radius Protocol No. BA058-05-005 “A Randomized, Double-Blind, Placebo
Controlled, Phase 2 Study of BA058 Administered as a Coated Transdermal
Microarray Delivery System (BA058 Transdermal) in Healthy Postmenopausal Women
with Osteoporosis”  (the “Protocol”).

 

1.              Subject to Paragraph 3, Radius hereby agrees to defend,
indemnify and hold harmless [CLINICAL STUDY SITE NAME] (“Clinical Study Site”),
including its officers and administrators, employees and agents, including the
Principal Investigator and his/her co-investigators and assistants in the Study
(collectively, “Indemnitees”) from and against any and all damages, suits,
judgments, and liabilities (including expenses and reasonable attorneys’ fees)
(collectively, “Losses”) arising from or related to any third party claims of
injury, illness or adverse side effects to a patient in the Study that are
attributable to the Study Drug.  The indemnification obligation set forth in
this Paragraph 1 shall not apply in the event and to the extent that:  (a) such
Loss(es) arose as a result of intentional misconduct or negligence by
Indemnitees; or (b) the Principal Investigator and those assisting him/her did
not adhere to the terms of the Protocol and to Radius’ written instructions
relative to the use of Study Drug or failed to employ reasonable care in the
conduct of the Study in conformity with the generally accepted standards of the
medical community or violated any applicable laws or regulations in any material
respect.  For purposes of this Paragraph 1, a violation shall be deemed
“material” if it adversely affects the safety, health or welfare of Study
subjects.

 

2.              In the event a patient participating in the Study suffers an
illness or injury which the Principal Investigator and Radius reasonably
determine to be an adverse reaction directly associated with the Study Drug, and
not due to a reason other than the Study Drug, then subject to the provisions of
Paragraph 3, Radius shall pay all necessary and reasonable medical and hospital
expenses directly associated with the medical treatment of such adverse

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

reaction which are in excess of that portion covered by the patient’s own
insurance or other insurance, or third-party payment programs.  In the event
diagnostic procedures are required to determine the etiology of the patient’s
symptoms, Radius shall pay the reasonable expense of such diagnostic work-up
without regard to the final diagnosis, so long as Radius agrees to the need for
the diagnostic work-up but Radius shall not be responsible for expenses
connected with the subsequent treatment of the patient if the work-up
establishes that the patient’s symptomology is not related to the administration
of the Study Drug.  Payments under this Paragraph 2 shall be in addition to any
payments specified in Paragraph 1.

 

3.              To receive the benefit of Paragraph 1 or Paragraph 2, the
appropriate personnel at Clinical Study Site must (a) promptly notify Nordic
Bioscience and Sponsor in writing of any claim of injury, illness, adverse side
effects or adverse reaction to the Study Drug; provided, that failure to give
such notice shall not relieve Radius of its obligations under Paragraph 1 or
Paragraph 2 except where, and solely to the extent that, such failure actually
and materially prejudices the rights of Radius; (b) tender to Radius (and its
insurer) full authority to defend or settle the claim or suit; provided that no
settlement requiring any admission by an Indemnitee or that imposes any
obligation on an Indemnitee shall be made without the Indemnitee’s consent; and
(c) cooperate fully with Radius in its handling of such claim or suit.  A
Clinical Study Site’s failure to perform its obligations under this Paragraph 3
shall relieve Radius of its obligations under Paragraphs 1 and 2. [Radius will
reimburse Indemnitees for all reasonable expenses incurred at Radius’ request in
connection with this Paragraph 3 except to the extent and in the proportion that
Indemnitees are responsible under Paragraph 1].

 

4.              Any notice to Radius shall be in writing and shall be deemed
given to Radius when delivered by hand or sent by internationally recognized
overnight courier (such mailed or courier notice to be effective on the date
which is two (2) business days after the date of mailing) or sent by facsimile
(such notice sent by telefax to be effective one (1) business day after sending,
if immediately confirmed by overnight courier as aforesaid), in each case
addressed to the following addresses: Radius Health, Inc., 201 Broadway,
6th Floor, Cambridge, MA 02139 USA Attn: [              ], Fax No.:
01.617.551.4701; Phone No.: 01.617.444.1834.

 

IN WITNESS WHEREOF, the undersigned has executed this letter intending it to
take effect as of                       , 2010.

 

 

RADIUS HEALTH, INC.

 

 

 

By:

 

 

Name, Title

 

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

Attachment L

 

Cash Budget: TRANSDERMAL_BUDGET_V3.1_26April-2012

 

--------------------------------------------------------------------------------

(1) The procedures for the Follow-up visit (Visit 10) for Study BA058-05-003
will serve as the procedures performed at Day 1 (for Study BA058-05-005).  The
consent form will need to be signed if it was not signed during the
End-of-Treatment Visit (Visit 9) of Study BA058-05-003.

(2) Interim or symptom directed physical examinations may be conducted at other
time points to assess adverse events or clinical laboratory abnormalities.

(3) Vital signs (blood pressure, pulse rate, body temperature, and respiration
rate) are to be recorded at each study visit.  Only the blood pressure
assessment on Day 1 (Visit 10) needs to be orthostatic.  Height is to be
measured on Day 1 (Visit 10) and Month 6 in the standing position using a
medical stadiometer.  Weight is to be measured on Day 1 (Visit 10) and Month 6. 
Orthostatic blood pressure is to be measured initially after 5 minutes in the
supine position and then again after standing for three minutes.

(4) All routine urinalysis will be performed on a sample freshly voided during
the clinic visit.

(5) These blood samples are to be obtained under fasting conditions (N.P.O. for
8 hours; water is acceptable) in the morning of each scheduled study visit.

(6) Includes blood samples for PINP, bone-specific alkaline phosphatase, serum
osteocalcin and CTX.

(7) Twenty-four hour urine collection will be used for urinary calcium and
urinary creatinine measurements. Subjects will discard the 1st void and begin a
24-hour urine collection the day prior to the clinic visit.

(8) Each DXA for a given subject should be performed on the same machine, and if
available, preferably by the same technician

(9)   Each DXA for a given subject should be performed on the same machine, and
if available, preferably by the same technician.  Only subjects who had wrist
DXA assessments in Study BA058-05-003 will have wrist DXAs performed.

(10) The subjects will maintain a diary throughout the study to record missed
doses of medication (including supplements) on a weekly basis; the diaries are
to be reviewed with the subject at each study visit.

 

[*] Certain information in this document has been omitted and filed separately
with the Securities and Exchange Commission. Confidential treatment has been
requested with respect to the omitted portions.

 

--------------------------------------------------------------------------------

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 1 TO WORK STATEMENT NB-3

 

RADIUS HEALTH, INC., a Delaware corporation (“Radius”) and NORDIC BIOSCIENCE
CLINICAL DEVELOPMENT VII A/S, a Danish corporation (“NB”) that is a wholly-owned
subsidiary of Nordic Bioscience Clinical Development A/S entered into a Clinical
Trial Services Agreement dated March 29, 2011 (“Agreement”) and Work Statement
NB-3 under the Agreement (“Work Statement NB-3”) as of February 21, 2013
(“Effective Date”)

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 1 to Work Statement NB-3 (“Amendment No. 1”)
effective as of February 28, 2014 (“Amendment Date”). Capitalized terms used in
this Amendment No. 3 and not defined herein are used with the meanings ascribed
to them in the Agreement and Work Statement NB-3.

 

NOW THEREFORE, in consideration of the mutual promises contained in the
Agreement and for other good and valuable consideration the receipt and adequacy
of which each of the parties does hereby acknowledge, the parties hereby agree
to the terms of this Amendment No. 1 to Work Statement NB-3 as follows:

 

1.  Addition of Period 2 to NB-3.  (a)  At Radius’ request, NB will contract
with up to 28 CCBR and non-CCBR Sites to enroll patients in a Period 2 extension
of the clinical study that is the subject of Work Statement NB-3 entitled:
BA058-05-005 “An Extension Study to Evaluate 24 Months of Standard-of-Care
Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo
Treatment in Protocol BA058-05-00” (Attachment 3 to the Agreement).  Radius
wishes to provide for payment to NB for Services during Period 2 under this
Amendment No. 1.

 

(b) Attachment A to Work Statement NB-3 is amended to add Study Assumptions for
Period 2 immediately following the Payment Schedule table for Period 1
(Attachment 1 to the Agreement).

 

(c)  Attachment B to Work Statement NB-3 is amended to add Payment Schedule for
Period 2 immediately following the final paragraph (Attachment 2 to the
Agreement).

 

This Amendment No. 1 to Work Statement NB-3 contains the following Attachments,
each of which is made a part hereof:

 

Attachment 1 — Specifications/Key Assumptions/Services/Division of

Responsibilities/Timeline Specifications

Attachment 2 — Budgets, Fees, Pass-through Costs, and Payment Schedule

Attachment 3 — Protocol

 

2.  Ratification.  Except to the extent expressly amended by this Amendment
No. 1, all of the terms, provisions and conditions of the Agreement and Work
Statement NB-3 are hereby ratified and confirmed and shall remain in full force
and effect.  The term “Work Statement NB-3”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-3 as amended by this
Amendment No. 1.

 

3.  General.  This Amendment No. 1 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument.

 

1

--------------------------------------------------------------------------------

 

IN WITNESS WHEREOF the parties have caused this Amendment No. 1 to be executed
by their respective duly authorized officers, and have duly delivered and
executed this Amendment No. 1 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL

DEVELOPMENT VII A/S

 

 

 

  /s/ Robert E. Ward

 

  /s/ Jeppe R. Andersen

By: Robert E. Ward

 

By: Jeppe R. Andersen

Title: Chief Executive Officer

 

Title: Chief Executive Officer

 

 

 

Notice Address

 

Notice Address

Radius Health, Inc.

 

Nordic Bioscience Clinical Development VII A/S

201 Broadway, 6th Floor

 

Herlev Hovedgade 207

Cambridge, MA 02139

 

2730 Herlev

USA

 

Denmark

Attn: President

 

Attn: Clinical Trial Leader & Medical Advisor /

Clinical Studies

Phone: 01.617.444.1834

 

Phone: 45.4452.5251

Fax: 01.617.551.4701

 

Fax: 45.4452.525

 

2

--------------------------------------------------------------------------------

 

Amendment No. 1 to Work Statement NB-3

Attachment 1

Specifications/Key Assumptions/Services/Division of Responsibilities/Timeline
Specifications

Study Assumptions for Period 2

Radius Health, Inc.

 

Protocol:  BA058-05-005, “An Extension Study to Evaluate 24 Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-00”

 

Protocol Number: BA058-05-005

Number of Sites:

28

 

Argentina

 

1

Brazil

 

5

Czech Republic

 

3

Denmark

 

3

Estonia

 

2

Hong Kong

 

1

Lithuania

 

1

Poland

 

6

Romania

 

1

USA

 

5

 

3

--------------------------------------------------------------------------------

 

Clinical Trial Timeline and Budget

 

Page 1 of 2

RADIUS

BA058-05-005 Amendment 1 (Period 2)

Protocol 05 February 2013

Cost Proposal 02 April 2013

 

Sponsor:

 

RADIUS

 

 

 

Protocol ID:

 

BA058-05-005 Amendment 1 (Period 2)

 

 

 

Development Phase:

 

III

 

 

 

Disease:

 

Osteoporosis

 

 

 

Total # of Randomized and completed subjects

 

925

 

 

 

Nordic Start Study Activity

 

1-Mar-13

 

 

 

Expected Date of FPFV:

 

1-May-13

 

 

 

Expected Length of Recruitment (months):

 

18

 

 

 

Treatment duration (months)

 

18

 

 

 

Follow-up duration (months)

 

1

 

 

 

Close Out (months)

 

Transferred from period 1

 

 

 

Duration of Nordic Involvement

 

37

 

 

 

Number of visits per patient:

 

2.5

 

 

 

Number of Countries:

 

10

 

Ar, Br, Dk, Cz, Ee, Li, Po, Ro, HK, USA

 

Number of Sites:

 

28

 

Ar x 1, Br x 5, Dk x 3, Cz x 3, Ee x 2, Li x 1, Po x 6, Ro x 1, HK x 1, USA x 5

 

 

Total Budget 

 

EURO

 

 

 

Clinic Fee

 

1,802,138

 

925 subjects

 

CRO Activities (Nordic Bioscience)

 

1,165,500

 

 

 

Central Lab Fee (Synarc Lab)

 

0

 

No lab tests to be performed

 

EDC system

 

 

 

Pass through. Estimated to be below 100,000 Euro

 

Calcium and D

 

 

 

Pass through. Estimated to be 15 Euro per month per subject

 

Alendronate

 

 

 

Pass through. Estimated to be 30 Euro per month per subject

 

Total Budget (Euro)

 

2,967,638

 

 

 

 

 

 

USD

 

 

 

Central Imaging Reading (Synarc Imaging)

 

527,740

 

Scalable and invoiced as such + shipment estimated 41,617 USD

 

Total Budget (USD)

 

527,740

 

 

 

 

4

--------------------------------------------------------------------------------

 

Page 2 of 2

 

Pass through Cost

 

EURO

 

 

 

Monitoring Travel Expenses & Accommodations/ other travels

 

Included

 

 

 

Translation

 

Included

 

 

 

Investigator Meeting

 

NA

 

 

 

Alendronate and calcium/ D supllement

 

Not included

 

 

 

Image shipments

 

Not included

 

 

 

Submission Fee to ERC and CA

 

Not included

 

 

 

EDC system

 

Not included

 

 

 

Data Monitoring Committe

 

Not included

 

 

 

Patient insurance

 

Not included

 

 

 

Medical writing

 

Not included

 

 

 

External advisory Board

 

Not included

 

 

 

Statistical Data analysis and Clinical Study Report

 

Not included

 

 

 

 

Payment schedule

 

Euro

 

 

 

 

 

 

 

 

 

Upfront

 

222,573

 

 

 

1,243 per enrolled subject

 

1,149,775

 

 

 

60,514 per month for 19 months

 

1,149,766

 

 

 

Rest

 

445,524

 

 

 

 

 

2,967,638

 

 

 

 

5

--------------------------------------------------------------------------------

 

Amendment No. 1 to Work Statement NB-3

Attachment B

Budgets, Fees, Pass-through Costs, and Payment Schedule*

For Period 2

 

Protocol:  BA058-05-005, “An Extension Study to Evaluate 24 Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-00”

 

The Cash budget is Euro 2,967,638 and USD 527,740

 

The Bonus Equity Payment Amount budget is Euro 2,967,638 and USD 527,740

 

The Cash budget will be paid as follows:

 

·                  7.5% (Euro 222,573) upon execution.

·                  39% (Euro 1,149,775) of the Euro cash budget will be paid
during enrollment at Euro 1,243 per randomized patients at all non-US sites (the
SITES).

·                  The USD budget will be paid according to invoices received
from Synarc Inc.

·                  39% (Euro 1,149,766) of the Euro cash budget will be paid on
a monthly basis over 19 months starting after patient randomization is completed
with Euro 60,514 per month.

·                  The USD budget will be paid according to invoices received
from Synarc Inc.

·                  15% (Euro 445,524) of the Euro cash budget will be paid when
the database is locked and transferred to and accepted by Radius.

 

Pass through costs will be invoiced on a monthly basis.

 

The Equity budget will be paid in concert with the cash payment after the same
model as for Work Statement NB-1, NB-2 and NB-3 (Period 1) under an amended
Stock Issuance Agreement modeled on the Amended and Restated Stock Issuance
Agreement entered into by the parties as of May 16, 2011.

 

The pricing specified in this Budget is calculated based upon 925 subjects
randomized and completed but will be adjusted for the number of completed
patients greater or less than 925 subjects as follows (i) on a fully pro rata
basis for the Clinic Fee and the Central Imaging Reading Fee; and (ii) by an
amount of euro 487 per subject for the CRO Activities Fee. Should greater than
925 patients be randomized into the study, Euro 1,243 per patient shall be paid
at the time of randomization of the additional patients. Thereafter, at the time
of completion of patient randomization for the study, the monthly payments over
the remaining 19 months of clinic activities shall be adjusted to reflect the
actual number of randomized patients but also factoring in the actual drop-out
rate at the time of completion of patient randomization and preserving a 15%
final payment amount when the database is locked and transferred to Radius. The
rate of drop-outs will be monitored over the 19 month period and appropriate
adjustments will be made on a quarterly basis to the monthly payment amount as
well as the final payment amount to reflect a higher or lower drop-out rate
following completion of patient randomization according to following table.

 

6

--------------------------------------------------------------------------------

 

Dropout time

 

Payment (if no radiology performed)

 

Payment (if radiology performed)

 

 

 

 

 

After Visit 3, before Visit 4

 

EUR 643 (33% of the total Clinic Fee)

 

EUR 1,123.5 (58% of the total Clinic Fee)

 

 

 

 

 

After Visit 4, before Visit 5

 

EUR 1,052 (54% of the total Clinic Fee)

 

EUR 1,535.8 (78.88% of the total Clinic Fee)

 

 

 

 

 

After Visit 5

 

n/a radiology is mandatory

 

EUR 1,948 (100% of the total Clinic Fee)*

 

--------------------------------------------------------------------------------

*The additional payment for radiology shall not be owed for any patient that is
lost to follow-up and no radiology is completed

 

The Cash Budget and the Bonus Equity Payment Amount shall be reduced by an
amount of euro 1,948 per subject for Clinic Activities not performed at the
SITES for any patients enrolled in the United States. Such reduction to be
applied in pro rata installments to monthly payments after patient randomization
is completed.  Otherwise, all pricing will be adjusted on a pro rata fashion to
reflect the actual study activities completed by the study subjects.

 

7

--------------------------------------------------------------------------------

 

[g17732le25i001.gif]

 

CLINICAL STUDY PROTOCOL

 

An Extension Study to Evaluate 24 Months of Standard-of-Care Osteoporosis
Management Following Completion of 18 Months of BA058 or Placebo Treatment in
Protocol BA058-05-003

 

This study will be conducted according to the protocol and in compliance with
Good Clinical Practice, the ethical principles stated in the Declaration of
Helsinki, and other applicable regulatory requirements.

 

Protocol Number:

Protocol BA058-05-005

Protocol Date (Version):

Original (23 July 2012)

Amendment 1, Version 1 (13 February 2013)

EudraCT Number

2012-002216-10

IND Number:

73,176

Study Sponsor:

Radius Health, Inc.

201 Broadway, 6th Floor

Cambridge, MA 02139, USA

Tel: 617.551.4700. Fax: 617.551.4701

Sponsor Medical Monitor:

Louis Brenner, MD

Chief Medical Officer, Radius Health, Inc.

Tel: 617.551.4006. Fax: 617.551.4701.

Email: lbrenner@radiuspharm.com

Study Safety Officer

Bente Juel Riis, MD

Medical Advisor, Nordic Bioscience A/S

Tel: +45 22 90 13 17. Fax: +41 91 970 2988

Email: bjr@nordicbioscience.com

Contract Research Organization (CRO):

Nordic Bioscience A/S

Herlev Hovedgade 207

2730 Herlev, Denmark

Tel: +45 4452 5252. Fax: +45 4452 5251

 

Disclosure Statement

 

This document contains information that is confidential and proprietary to
Radius Health, Incorporated (RADIUS). This information is being provided to you
solely for the purpose of evaluation and/or conducting a clinical trial for
RADIUS. You may disclose the contents of this document only to study personnel
under your supervision and/or to your institutional review board(s) or ethics
committee(s) who need to know the contents for this purpose and who have been
advised on the confidential nature of the document.

 

8

--------------------------------------------------------------------------------

 

PROTOCOL SYNOPSIS

 

Title:      An Extension Study to Evaluate 24 Months of Standard-of-Care
Osteoporosis Management Following Completion of 18 Months of BA058 or Placebo
Treatment in Protocol BA058-05-003

 

Protocol Number:  BA058-05-005

 

Test Drug:  BA058 Injection

 

Study Objectives:

 

The primary objective of this study is to collect clinical information regarding
six months of treatment with alendronate, in subjects who have previously
received 18 months of blinded treatment with BA058 Injection or Placebo in Study
BA058-05-003.  Safety data will be obtained via clinical, laboratory and
radiologic assessments.  Following the initial six months of treatment in the
study, subjects will then enter the long-term observational phase of the study
during which subjects will continue to receive alendronate treatment for an
additional 18 months (for a total of 24 months).

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate in
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on BMD change and osteoporosis
status associated with 24 months of treatment with alendronate after 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

The analysis performed at six months of this Extension Study will be used as a
follow-up to the 18 month fracture endpoint for Study BA058-05-003.  The
analyses performed on data in this study will be descriptive in nature.  Full
details of the statistical procedures to be used will be provided in the
Statistical Analysis Plan.

 

Study Population:

 

Subjects with postmenopausal osteoporosis who completed the End-of-Treatment
Visit (Visit 9) for Study BA058-05-003 and were previously randomized to either
blinded BA058 Injection 80 µg or blinded Placebo are eligible for inclusion into
this Extension Study provided that they fulfill the Inclusion/Exclusion criteria
described below.

 

Inclusion/Exclusion Criteria

 

Otherwise healthy ambulatory postmenopausal women who participated in, and who
completed 18 months of treatment with either blinded BA058 Injection 80 µg or
blinded Placebo in Study BA058-05-003, are scheduled to complete or have
completed the End-of-Treatment visit (Visit 9 in Study BA058-05-003), and who
have provided a new written informed consent for the Extension Study, are
eligible for enrollment into this study.  Participants must be no more than 40
days from Visit 9 in Study BA058-05-003 to be eligible for this study.  The
physical examinations and clinical laboratory measurements from the
End-of-Treatment visit from Protocol BA058-05-003 (Visit 9) of the BA058-

 

9

--------------------------------------------------------------------------------

 

05-003 study will provide baseline data for this Extension Study.  In addition,
the subjects must, in the opinion of the Investigator, be appropriate candidates
for further osteoporosis management.

 

Subjects will not be enrolled if they experienced a treatment-related SAE as
assessed by the Investigator, or if they were withdrawn from Study BA058-05-003
for any reason.  Subjects who are not candidates for alendronate treatment will
receive standard-of-care management determined to be appropriate by the
Investigator.  Specific inclusion and exclusion criteria are described in
Section 4.1 and Section 4.2, respectively.

 

Study Design and Methodology:

 

Number of Subjects

 

All subjects who were randomized to the BA058 Injection 80 µg/Placebo arms in
Study BA058-05-003, and who completed 18 months of treatment will be offered the
opportunity to participate in this study.  There will, therefore, be a potential
maximum of 1,600 subjects eligible to be enrolled in this study.

 

Design

 

This study will be an open-label extension of Study BA058-05-003.  The purpose
of the study is to provide longer term safety data, fracture data and BMD data
after six months of treatment with alendronate, in otherwise healthy ambulatory
postmenopausal women with severe osteoporosis who have previously received 18
months of blinded treatment with BA058 Injection or Placebo.  The analysis
performed at six months will be used as a follow-up to the 18 month fracture
endpoint for Study BA058-05-003.  In addition, this study will examine changes
in osteoporosis status after 24 months of treatment with alendronate in
otherwise healthy ambulatory women with severe osteoporosis who have previously
received 18 months of blinded treatment with BA058 Injection/Placebo.  The
analysis performed at 24 months will be descriptive in nature.

 

Subjects randomized to BA058 Injection 80 µg/Placebo in Study BA058-05-003 and
who are candidates for ongoing osteoporosis care, will receive six months of
treatment with oral alendronate at a total dose of 70 mg once per week for 24
months.  All subjects will undergo protocol specified procedures (Section 7.0,
Appendix 14.1 and 14.2) including BMD and fracture assessment.  The study design
is presented in Figure 1, below.

 

10

--------------------------------------------------------------------------------

 

Figure 1:  Protocol BA058-05-005 Study Design

 

[g17732le25i002.jpg]

 

In this study, the Follow-up Visit from the 18 month study (Visit 10 from Study
BA058-05-003) will serve as the Day 1 Visit (Visit 1) for this six month
Extension Study (Study BA058-05-005).

 

Following the initial six months of treatment, subjects will enter the long-term
observational phase of this study during which the subjects will continue to
receive alendronate treatment for an additional 18 months.  During the long-term
follow-up of this study, subjects will continue to undergo study related
procedures as outlined in Section 14.1 and Section 14.2.

 

All subjects will continue to take calcium and vitamin D supplementation
throughout the Extension Study.

 

Study Visits

 

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility
of participating in the Extension Study will be discussed with subjects
randomized to BA058 80 µg/Placebo.  This Extension Study will be comprised of
standard-of-care osteoporosis management, including 24 months of treatment with
alendronate.  In the month between Visit 9 and Visit 10 (between months 18 and
19 of Study BA058-05-003), the Investigator will consider the results of the
assessments performed at Visit 9, including a local review of BMD, and determine
if alendronate is appropriate for the subject, as part of this Extension Study.

 

At the Follow-up (Visit 10 for Protocol BA058-05-003, Day 1 for Protocol
BA058-05-005) subjects; who were randomized to BA058 Injection 80 µg/Placebo,
who fulfill the inclusion/exclusion criteria (Section 4.1 and Section 4.2), and
who have agreed to participate in the Extension Study; will sign the Informed
Consent Form and be enrolled in the study.

 

Alendronate is the recommended osteoporosis treatment for this Extension Study. 
Subjects who have been determined by the Investigator to be candidates for
alendronate therapy will receive open-label oral alendronate treatment at a
total dose of 70 mg once per week for 24 months.  Subjects will be instructed to
take their first dose of alendronate for Study BA058-05-005 in the morning, on
the day following their Day 1 visit.  Following the initial six months of
treatment in this study, subjects will

 

11

--------------------------------------------------------------------------------

 

enter the long-term observational phase of this study, during which subjects
will continue to receive alendronate treatment for an additional 18 months.

 

All subjects will have clinic visits for study related procedures at Day 1,
Month 3, Month 6, Month 12, Month 18 and Month 24.  For the purpose of this
study one month is equal to 30 days.

 

Statistical Considerations:

 

Exploratory statistical analyses will assess longer term safety, fracture
incidence (including vertebral and non-vertebral fracture), and BMD change
following treatment with alendronate for six months after the completion of a
subject’s participation of 18 months in study BA058-05-003.

 

The analyses performed at six months will be used as a follow-up to the 18 month
fracture endpoint for Study BA058-05-003.  At this time-point, subjects will be
analyzed based on the randomization assignment in the BA058-05-003 study.  Other
analyses performed on the data in this study will be descriptive in nature.

 

Fractures and BMD Analyses

 

All specified endpoints will be summarized by treatment group and study period
using standard descriptive statistics (n, mean, SD, median, minimum, maximum or
n and %, as appropriate).  The fracture incidence; either clinically or
radiologically determined, based on clinical events or protocol-directed
vertebral x-rays at Month 6 of this Extension Study; will be tabulated.  In
addition, BMD results from the six months of treatment with alendronate will
also be tabulated based on the treatment arm they were randomized to in the
BA058-05-003 study, with additional tabular categories for results from the
entire contiguous 24 months from baseline of study BA058-05-003 through the end
of Study BA058-05-005, as well as the results during the 18 months of study
BA058-05-003, for subjects who eventually enter study BA058-05-005.  These
descriptive analyses will be conducted on all subjects with baseline and
post-baseline data.

 

Safety Analysis

 

Data will be summarized and tabulated based on the enrolled population for this
Extension Study.  All subjects enrolled in the Extension Study will be included
in the safety analysis that will be performed on the following parameters:

 

·                  Incidence and severity of AEs.

 

·                  Pathological changes in hematology, chemistry and urinalysis
data based on normal ranges supplied by the clinical laboratory, if applicable.

 

Safety assessments for changes in physical examination, vital signs, ECG, and
laboratory tests will be descriptively summarized by treatment and study
periods.  Concomitant medication classes will be categorized using World Health
Organization (WHO) drug dictionary and summarized by number and percent of
subjects using each class by treatment group.  All treatment emergent adverse
events (TEAEs) will be coded for system organ class (SOC) and preferred term
(PT) using MedDRA and the number (%) of subjects experiencing each AE (SOC/PT)
will be summarized by treatment, relationship to treatment, and severity.  All
serious adverse events (SAE) will be listed and the number (%) of subjects with
an SAE presented by treatment group.

 

Procedures and Assessments

 

Fractures and BMD

 

The End-of-Treatment (Visit 9) evaluations for vertebral fracture assessment,
non-vertebral fracture assessment and BMD from Study BA058-05-003 will serve as
the baseline evaluations in this study.  The Day 1 assessment will be concurrent
with the Follow-up Visit (Visit 10) for Study BA058-05-003.  Subjects will
return to the clinic for assessment of BMD at spine, hip and wrist (for those

 

12

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subjects who had wrist DXAs performed in Study BA058-05-003) at Month 6 and at
Month 24.  Clinical and radiographic assessments for fractures will be performed
at Month 6 and Month 24, and bone marker assessments of anabolism (PINP,
bone-specific alkaline phosphatase and osteocalcin) and resorption (CTX) will be
performed at Day 1 and Month 6.

 

Safety

 

Safety evaluations performed will include physical examinations, vital signs,
12-lead ECGs, clinical laboratory tests, and monitoring and recording of adverse
events.

 

Complete details of the study assessments are provided in Section 7.0, in the
Schedule of Visits and Procedures (Appendix 14.1) and in the Suggested Schedule
of Events and Procedures by Study Visit (Appendix 14.2).

 

Treatments Administered

 

Alendronate sodium (Fosamax®, Merck & Co., Inc., or other approved generic
manufacturer) 70 mg tablets for oral administration contain 91.35 mg of
alendronate monosodium salt trihydrate which is the molar equivalent of 70 mg
free acid and excipients.  Alendronate should be stored in a well-closed
container at room temperature, 15-30ºC.  The alendronate may be generic
substitutable approved versions which contain different inactive ingredients,
but the amount of active free alendronate must be equivalent to 70 mg. 
Alendronate for Europe, Hong Kong and the US will be sourced centrally;
alendronate for South America will be sourced locally by the medical center and
reimbursed by the Sponsor.

 

Calcium (500—1000 mg) and vitamin D (400—800 IU) supplements will be sourced
locally by the medical center and provided to the subjects at the expense of the
Sponsor. Subjects will continue to take calcium and vitamin D as they did in
Study BA058-05-003.

 

Duration of Subject Participation:

 

Participation in the initial phase of this study will be approximately six
months from enrollment to completion of the six month study evaluations. 
Participation for both the initial and observational phases of the study will be
approximately 24 months.  In combination with Study BA058-05-003, subjects will
participate in this clinical postmenopausal osteoporosis program for 43 to 44
months.  The first visit of Study BA058-05-005 will be concurrent with Visit 10
of Study BA058-05-003.

 

13

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TABLE OF CONTENTS

 

PROTOCOL SYNOPSIS

9

 

 

Table of Contents

14

 

 

List of Abbreviations

17

 

 

1.0

introduction

19

 

1.1

Background Information

19

 

1.2

Drug Under Study

20

 

 

1.2.1

Efficacy of Alendronate

20

 

 

1.2.2

Safety of Alendronate Sodium

20

 

1.3

Study Rationale and Selection of Doses

21

 

 

1.3.1

Study Rationale

21

 

 

1.3.2

Study Design

22

 

 

1.3.3

Study Population

22

 

 

1.3.4

Selection of Endpoints

22

 

 

1.3.5

Selection of Dose

22

 

 

 

2.0

STUDY OBJECTIVES

23

 

 

 

3.0

INVESTIGATIONAL PLAN

23

 

3.1

Overall Design and Study Plan

23

 

 

3.1.1

Treatment Period

24

 

 

 

4.0

SELECTION OF STUDY POPULATION

25

 

4.1

Number of Subjects

25

 

4.2

Inclusion Criteria

25

 

4.3

Exclusion Criteria

25

 

4.4

Withdrawal of Subjects from the Study

26

 

4.5

Temporary Suspension of Treatment

26

 

4.6

Replacement of Subjects

26

 

 

 

5.0

STUDY TREATMENTS

27

 

5.1

Study Medications

27

 

 

5.1.1

Alendronate

27

 

 

5.1.1.1

Restrictions on Alendronate Use

27

 

 

5.1.2

Calcium and Vitamin D Supplements

27

 

5.2

Packaging, Labeling and Storage

27

 

 

5.2.1

Storage

27

 

14

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5.3

Treatment Assignment

27

 

5.4

Study Medication Administration

28

 

 

5.4.1

Alendronate Administration

28

 

5.5

Treatment Compliance

28

 

5.6

Unblinding of Study Medication

28

 

 

 

6.0

CONCOMITANT MEDICATIONS

28

 

6.1

Concomitant Medications

28

 

6.2

Prohibited Medications

29

 

 

 

 

7.0

STUDY ASSESSMENTS

29

 

7.1

Clinical Procedures/Assessments

29

 

 

7.1.1

Informed Consent

29

 

 

7.1.2

Recent Health Status

30

 

 

7.1.3

Vital Signs

30

 

 

7.1.4

Height and Weight

30

 

 

7.1.5

Orthostatic Blood Pressure and Heart Rate

30

 

 

7.1.6

Electrocardiogram

30

 

 

7.1.7

Clinical Laboratory Evaluations

30

 

 

7.1.8

Clinical Chemistry and Urinalysis (Dipstick)

31

 

 

7.1.9

Hematology

31

 

 

7.1.10

Coagulation

32

 

 

7.1.11

24-Hour Urine Collection

32

 

 

7.1.12

Bone Mineral Density

32

 

 

7.1.13

Serum Markers of Bone Metabolism

32

 

 

7.1.14

Clinical and Radiologic Evaluation of Fractures

33

 

 

7.1.15

BA058 Antibody Assessments

33

 

 

7.1.16

Subject Diaries

33

 

 

7.1.17

Activity and Diet

33

 

 

 

8.0

ADVERSE EVENTS AND SAFETY EVALUATION

33

 

8.1

Definitions, Documentation, and Reporting

34

 

 

8.1.1

Adverse Event Definition

34

 

 

8.1.2

Serious Adverse Event Definition

34

 

8.2

Monitoring of Adverse Events and Period of Observation

35

 

8.3

Procedures for Recording and Reporting AEs and SAEs

35

 

8.4

Rules for Suspension of the Study

36

 

 

 

9.0

Statistical Procedures

37

 

9.1

Sample Size

37

 

9.2

Randomization, Stratification and Blinding

37

 

9.3

Populations for Analysis

37

 

 

9.3.1

Safety Population

37

 

9.4

Procedures for Handling Missing, Unused, and Spurious Data

37

 

15

--------------------------------------------------------------------------------

 

 

9.5

Statistical Methods

38

 

 

9.5.1

Statistical Considerations

38

 

 

9.5.2

Baseline Comparisons

38

 

 

9.5.3

Fractures and BMD Analysis

38

 

 

9.5.4

Safety Analysis

38

 

 

9.5.5

Procedures for Reporting Deviations to Original Statistical Analysis Plan

39

 

9.6

Data Oversight

39

 

 

9.6.1

Central Review of Radiographs and DXA Scans

39

 

 

 

10.0

ADMINISTRATIVE REQUIREMENTS

39

 

10.1

Good Clinical Practice

39

 

10.2

Ethical Considerations

39

 

10.3

Subject Information and Informed Consent

40

 

10.4

Protocol Compliance

40

 

10.5

Case Report Form Completion

40

 

10.6

Source Documents

41

 

10.7

Study Monitoring

41

 

10.8

On-Site Audits

41

 

10.9

Drug Accountability

41

 

10.10

Record Retention

42

 

10.11

Study Termination

42

 

10.12

Liability and Insurance

42

 

 

 

11.0

USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

43

 

11.1

Use of Information

43

 

11.2

Publication

43

 

 

 

12.0

INVESTIGATOR AGREEMENT

44

 

 

 

13.0

References

45

 

 

 

14.0

APPENDICES

47

 

14.1

Schedule of Visits and Procedures

48

 

14.2

Suggested Schedule of Events and Procedures by Study Visit

49

 

14.3

Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria

57

 

16

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LIST OF ABBREVIATIONS

 

Abbreviation

 

Term

°C

 

Degree Celsius

°F

 

Degree Fahrenheit

µg

 

Microgram

µmol

 

Micromole

AE

 

Adverse event

ALT

 

Alanine aminotransferase

AST

 

Aspartate aminotransferase

BMD

 

Bone mineral density

BMI

 

Body mass index

bpm

 

Beats per minute

BSAP

 

Bone-specific alkaline phosphatase

BUN

 

Blood urea nitrogen

cm

 

Centimeter

CPK

 

Creatine phosphokinase

CRF

 

Case report form

CRO

 

Contract research organization

CTX

 

C-telopeptides of type 1 collagen crosslinks (serum)

DXA

 

Dual energy x-ray absorptiometry

ECG

 

Electrocardiogram

eCRF

 

Electronic case report form

FDA

 

Food and Drug Administration

g

 

Gram

GCP

 

Good clinical practice

GGT

 

Gamma-glutamyltranspeptidase

GLP

 

Good laboratory practice

GMP

 

Good manufacturing practice

ICH

 

International Conference on Harmonization

IEC

 

Independent ethics committee

IRB

 

Institutional review board

ITT

 

Intent-to-treat

IU

 

International unit

IV

 

Intravenous

IVRS

 

Interactive voice response system

kg

 

Kilogram

L

 

Liter

LDH

 

Lactate dehydrogenase

MCH

 

Mean corpuscular hemoglobin

MCHC

 

Mean corpuscular hemoglobin concentration

 

17

--------------------------------------------------------------------------------

 

Abbreviation

 

Term

MCV

 

Mean corpuscular volume

MedDRA

 

Medical dictionary for regulatory activities

µL

 

Microliter

mg

 

Milligram

mL

 

Milliliter

mmHg

 

Millimeter of mercury

msec

 

Millisecond

NPO

 

Nothing by mouth

ng

 

Nanogram

ONJ

 

Osteonecrosis of the jaw

PA

 

Posterior-anterior

PD

 

Pharmacodynamic

pg

 

Picogram

PINP

 

N-terminal propeptide of type I procollagen

PK

 

Pharmacokinetic

PT

 

Prothrombin time

PTH

 

Parathyroid hormone

PTHrP

 

Parathyroid hormone related peptide

PTT

 

Partial thromboplastin time

PUBs

 

Upper gastrointestinal perforations, ulcers and bleeds

QT

 

Total depolarization and repolarization time

QTc

 

Total depolarization and repolarization time corrected with heart rate

RBC

 

Red blood cell

SAE

 

Serious adverse event

SC

 

Subcutaneous

SD

 

Standard deviation

SERMs

 

Selective estrogen receptor modulators

SOC

 

System organ class

SOP

 

Standard operating procedure

TEAEs

 

Treatment emergent adverse events

ULN

 

Upper Limit of Normal

WBC

 

White blood cells

WHO

 

World Health Organization

 

18

--------------------------------------------------------------------------------

 

1.0                         INTRODUCTION

 

1.1                         Background Information

 

Osteoporosis is a systemic skeletal disease characterized by low bone mass and
microarchitectural deterioration of bone tissue which leads to enhanced
fragility and increased risk of fractures (Rizzoli, 2001).  It is estimated that
over 200 million people worldwide have osteoporosis (Reginster, 2006) and
osteoporosis causes more than 8.9 million fractures worldwide, of which more
than 4.5 million occur in the Americas and Europe (WHO Scientific Group, 2007). 
The vast majority of osteoporotic fractures occur in elderly women and incidence
increases markedly with age.  Most fractures occur at the spine, wrist and hip. 
Of these, hip fractures carry the highest morbidity and mortality.  In 1990, the
total number of hip fractures in men and women was estimated to be 1.26 million
worldwide, and it is estimated that this number will increase to 3.6 million by
2025 and to 4.5 million by 2050 (Gullberg, 1997).

 

Subject enrolled in this Extension Study will have completed 18 months of
treatment with BA058 Injection 80 µg/Placebo.  BA058 is a synthetic 34 amino
acid analog of parathyroid hormone related peptide(PTHrP), with molecular
modifications of specific amino acids, and is under clinical development for the
prevention of fractures in postmenopausal women with severe osteoporosis who are
at a risk for fracture.  BA058 shows particular potential for reversing bone
loss at both the spine and the hip, the site of the most debilitating
osteoporotic fractures in elderly women.  BA058 is a synthetic analog of PTHrP
(1-34) designed to give a greater anabolic effect than human parathyroid hormone
(hPTH).  Initial in vitro and in vivo studies identified BA058 as displaying
bone anabolic properties without a significant hypercalcemic effect.  In humans,
BA058 has different pharmacokinetics (PK) and pharmacodynamics (PD) properties
than hPTH(1-34) and has been shown in a Phase 2 study (BA058-05-002) to have
similar or greater efficacy in restoring bone mineral density (BMD) in
individuals with osteoporosis than hPTH(1-34).  Overall, BA058 has been well
tolerated in previous studies.

 

This is an open-label extension of Study BA058-05-003.  Enrollment requires
previous participation in, and successful completion of, 18 months of treatment
with BA058 Injection 80 µg/Placebo in Study BA058-05-003.  The purpose of this
extension is to accumulate longer-term safety, fracture, and BMD data in
subjects who receive six months of standard-of-care osteoporosis treatment,
including treatment with alendronate, following 18 months of treatment with
blinded BA058/Placebo treatment.  Following the initial six months of treatment
in this study, subjects will then enter the long-term observational phase of
this study during which the subjects will continue to receive alendronate
treatment for an additional 18 months.  The analyses performed at six months
will be used as a follow-up to the 18 month fracture endpoint for Study
BA058-05-003.  Other analyses performed on the data in this study will be
descriptive in nature.  Full details of the statistical procedures to be used
will be provided in the Statistical Analysis Plan.  Alendronate, a
bisphosphonate, is approved and marketed world-wide for the treatment and
prevention of osteoporosis in postmenopausal women.

 

19

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1.2                               Drug Under Study

 

1.2.1                     Efficacy of Alendronate

 

Alendronate is a bisphosphonate that acts as a specific inhibitor of
osteoclast-mediated bone resorption.  Bisphosphonates are synthetic analogs of
pyrophosphate that bind to the hydroxyapatite found in bone.  At the cellular
level, alendronate shows preferential localization to sites of bone resorption,
specifically under osteoclasts.  The osteoclasts adhere normally to the bone
surface but lack the ruffled border that is indicative of active resorption. 
Alendronate does not interfere with osteoclast recruitment or attachment, but it
does inhibit osteoclast activity. (Fosamax Package Insert)

 

Bisphosphonates including alendronate are widely used to treat osteoporosis.  In
animal models, minipigs treated with alendronate exhibited a direct correlation
between cancellous bone volume and bone strength (Lefage 1995).  In primates,
treatment with alendronate increased the strength of cancellous bone between 44
and 100% (the effect was dose dependent) when compared to vehicle, and also
increased bone mass (Balena 1993).  In dogs, this increase in bone mass occurred
without causing abnormalities in bone modeling of bone structure (Balena, 1996).

 

In postmenopausal women, alendronate has been demonstrated to increase bone
mineral density, decrease bone turnover and reduce the risk of fracture among
women with osteoporosis (Tucci, 1996; Devogelaer, 1996; Liberman, 1995).  The
therapeutic effects on bone density, remodeling and fracture prevention persist
following daily treatment at an oral dose of 10 mg for up to 10 years (Bone,
2004).  Studies have demonstrated that sequential treatment of osteoporosis with
one year of treatment with PTH followed by one year of treatment with
alendronate resulted in an increase in vertebral bone density that was
considerably greater than previously reported for alendronate alone (Rittmaster,
2000).  In subjects receiving PTH(1-84) followed by alendronate, there were
significant increases in BMD, in particular trabecular spine, when compared to
PTH(1-84) followed by placebo (31% vs. 14%, p<0.001) (Black, 2005).

 

1.2.2                     Safety of Alendronate Sodium

 

According to the US package insert for Fosamax® (alendronate sodium), in studies
of up to five years duration, adverse experiences usually were mild and
generally did not require discontinuation of therapy.  In a three-year,
placebo-controlled, double blind study in which 196 subjects were treated with
10 mg/day, discontinuation due to any adverse experience occurred in 4.1% of
subjects treated with alendronate, and 6% of 397 subjects treated with placebo. 
The most frequently reported adverse event (occurring in >2% of subjects treated
with alendronate) in this study were abdominal pain, musculoskeletal pain,
nausea, dyspepsia, constipation, diarrhea, flatulence, headache and acid
regurgitation.

 

Alendronate may cause local irritation of the upper gastrointestinal mucosa. 
Esophageal adverse experiences, such as esophagitis, esophageal ulcers and
esophageal erosions occasionally with bleeding and rarely followed by esophageal
stricture or perforation have been reported.  Osteonecrosis of the jaw (ONJ),
which can occur spontaneously, is generally associated with tooth extraction
and/or local infection with delayed healing, has been reported in subjects
taking alendronate.  For subjects requiring dental procedures, discontinuation
of alendronate therapy may reduce the risk for ONJ.

 

20

--------------------------------------------------------------------------------

 

Atypical, low-energy, or low trauma fractures of the femoral shaft have been
reported in bisphosphonate-treated patients.  These fractures can occur anywhere
in the femoral shaft from just below the lesser trochanter to above the
supracondylar flare and are transverse or short oblique in orientation without
evidence of comminution.  Causality has not been established as these fractures
also occur in osteoporotic patients who have not been treated with
bisphosphonates.

 

Atypical femur fractures most commonly occur with minimal or no trauma to the
affected area.  They may be bilateral and many patients report prodromal pain in
the affected area, usually presenting as dull, aching thigh pain, weeks to
months before a complete fracture occurs.  A number of reports note that
patients were also receiving treatment with glucocorticoids (e.g. prednisone) at
the time of fracture.

 

Any patient with a history of bisphosphonate exposure who presents with thigh or
groin pain should be suspected of having an atypical fracture and should be
evaluated to rule out an incomplete femur fracture.  Patients presenting with an
atypical fracture should also be assessed for symptoms and signs of fracture in
the contralateral limb.  Interruption of bisphosphonate therapy should be
considered, pending a risk/benefit assessment, on an individual basis.

 

According to the Summary of Product Characteristics for alendronate from the
EMA, the following adverse experiences have been reported in alendronate treated
subject during clinical trials and/or post-marketing use:

 

Common:  Headache, abdominal pain, dyspepsia, constipation, diarrhea,
flatulence, esophageal ulcer, dysphagia, abdominal distension, acid
regurgitation and musculoskeletal pain.

 

Uncommon:  Nausea, vomiting, gastritis, esophagitis, esophageal erosions,
melena, rash, pruritus and erythema.

 

Rare:  Hypersensitivity reactions including urticarial and angioedema,
symptomatic hypocalcemia (often in association with predisposing conditions),
uveitis, scleritis, episcleritis, esophageal stricture, oropharyngeal
ulceration, upper gastrointestinal perforations, ulcers and bleeds (PUBs), rash
with photosensitivity, osteonecrosis of the jaw, atypical subtrochanteric and
diaphyseal femoral fractures and transient symptoms as in an acute-phase
response (myalgia, malaise and rarely, fever), typically associated with
initiation of treatment.

 

1.3                               Study Rationale and Selection of Doses

 

1.3.1                     Study Rationale

 

The purpose of the study is to provide longer term safety data, fracture data
and BMD data after six months of treatment with alendronate, in otherwise
healthy ambulatory postmenopausal women with severe osteoporosis who have
previously received 18 months of blinded treatment with BA058 Injection or
Placebo.  Following the initial six months of treatment in this study, subjects
will enter the long-term observational phase of the study during which the
subjects will continue to receive alendronate for an additional 18 months.

 

21

--------------------------------------------------------------------------------

 

1.3.2                     Study Design

 

Subjects randomized to BA058 Injection 80 µg/Placebo, who have completed 18
months of treatment in Protocol BA058-05-003 and, who meet the
Inclusion/Exclusion criteria (Sections 4.2 and 4.3) are eligible to participate
in this study.  Subjects originally randomized to BA058 Injection 80 µg/Placebo
in Study BA058-05-003 and who are candidates for ongoing osteoporosis care, will
receive 24 months of daily open-label alendronate treatment at a total dose of
70 mg/week.

 

1.3.3                     Study Population

 

The study population in this protocol is comprised of otherwise healthy
ambulatory postmenopausal women who:

 

1.              have participated in Study BA058-05-003,

2.              were randomized to either BA058 Injection 80 µg/Placebo,

3.              have completed the End-of-Treatment Visit (Visit 9 in Study
BA058-05-003), and

4.              have provided a new written informed consent for this protocol.

 

Subjects will not be enrolled if they experienced treatment-related SAE or were
withdrawn from Study BA058-05-003 for any reason.

 

1.3.4                     Selection of Endpoints

 

The fracture incidence; either clinically or radiologically determined, based on
clinical events or protocol-directed vertebral x-rays at Month 6 of this
Extension Study; will be tabulated.  In addition, BMD results from the six
months of treatment with alendronate will also be tabulated, with additional
tabular categories for results from the entire contiguous 24 months from
baseline of study BA058-05-003 through the end of Study BA058-05-005, as well as
the results during the 18 months of study BA058-05-003, for subjects who
eventually enter study BA058-05-005. Bone formation (PINP, osteocalcin, BSAP)
and resorption (CTX) markers will also be assessed.  Clinical incidence of any
fracture and radiologic incidence of vertebral fracture will also be evaluated
at Month 24.  The End-of-Treatment (Visit 9) evaluations for BMD, vertebral
fracture, and non-vertebral fracture assessments from BA058-05-003 will serve as
the baseline evaluations in this study.

 

Subjects will be monitored for safety events and will have safety assessments
performed at each study visit.  At Month 6 and Month 24, BMD by DXA, as well as
clinical and radiologic assessment of the spine for assessment of fractures will
be performed.  Bone formation and resorption markers will also be assessed at
Day 1 and Month 6.  Further details of these assessments are in Section 7.0, and
in Appendix 14.1 and 14.2.

 

1.3.5                     Selection of Dose

 

The dose of alendronate (70 mg per week, oral) selected for this study is based
upon the recommended daily dose in the product’s prescribing information.

 

All enrolled subjects will also continue to receive calcium (500-1000 mg) and
vitamin D (400-800 IU) supplementation.

 

22

--------------------------------------------------------------------------------

 

2.0                         STUDY OBJECTIVES

 

The primary objective of this study is to evaluate data obtained following six
months of treatment with alendronate, in subjects who have previously received
18 months of blinded treatment with BA058 Injection 80 µg/Placebo.  Safety will
be evaluated with clinical, laboratory and radiologic assessment.     The
analysis at six months will be based on the treatment that subjects were
randomized to in the BA058-05-003 study.  Following the initial six months of
treatment in this study, subjects will then enter the long-term observational
phase of the study during which the subjects will continue to receive
alendronate treatment for an additional 18 months.

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate in
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on BMD change and osteoporosis
status associated with 24 months of treatment with alendronate after 18 months
of BA058 Injection 80 µg/Placebo.

 

The analysis performed at six months will be used as a follow-up to the 18 month
fracture endpoint for Study BA058-05-003.  Additional analyses performed on the
data in this study will be descriptive in nature.  Full details of the
statistical procedures to be used will be provided in the Statistical Analysis
Plan.

 

3.0                               INVESTIGATIONAL PLAN

 

3.1                               Overall Design and Study Plan

 

This study is an open-label extension of Study BA058-05-003.  Subjects and
Investigators who participate in Study BA058-05-005 will remain blinded to prior
treatment assignment as part of BA058-05-003.  At the End-of-Treatment visit
(Visit 9) for Study BA058-05-003, the possibility of participating in the
Extension Study will be discussed with subjects randomized to BA058 80
µg/Placebo.  The Extension Study will be comprised of an initial six months of
treatment with alendronate.  In the month between Visit 9 and Visit 10, the
Investigator will review the results of the assessments performed at Visit 9,
including a local interpretation of BMD, and determine if alendronate is
appropriate for the subject.  All subjects will continue to receive vitamin D
and calcium supplementation as they did in Study BA058-05-003.  The study design
is presented in Figure 2, below.

 

23

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Figure 2:  Protocol BA058-05-005 Study Design

 

[g17732le29i001.jpg]

 

Participation for both the initial and observational phases of the will be
approximately 24 months.  There are a total of six clinic visits during the
course of the study.

 

A brief summary of the study is provided below.  For a summary of the study
assessments to be performed, refer to Section 7.0 (Study Assessments) and to the
Schedule of Visits and Procedures (Appendix 14.1).  A more detailed description
of the study procedures on a by-visit basis is provided in Appendix 14.2
(Suggested Schedule of Events and Procedures by Study Visit).  A suggested order
of procedures is also provided in this schedule.

 

3.1.1                     Treatment Period

 

Subjects will enter into Study BA058-05-005 on Day 1, and Day 1 will also serve
as Visit 10 (the Follow-up Visit) for Study BA058-05-003.  The Informed Consent
must be signed prior to undergoing any BA058-05-005 study related procedures,
and may be signed at either Visit 9 or Visit 10 of Study BA058-05-003.  Subjects
who received BA058 Injection 80 µg/Placebo in Study BA058-05-003 will receive
six months of open-label oral alendronate treatment as part of this study
(BA058-05-005).  Following the initial six months of treatment in this study,
subjects will then enter the long-term observational phase of this study during
which the subjects will continue to receive osteoporosis care for an additional
18 months.

 

If determined by the Investigator to be appropriate, treatment will be by oral
administration of alendronate at a total dose of 70 mg once per week. Subjects
will be given a weekly diary card to record missed doses of medication including
calcium and vitamin D.

 

A total of six clinic visits are scheduled during the study (Day 1, Month 3,
Month 6, Month 12, Month 18 and Month 24).

 

24

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Subjects will be instructed to take their first dose of study drug for Study
BA058-05-005 in the morning on the day following their Day 1 visit (Day 2 of
this study).  Study subjects will continue calcium and vitamin D supplementation
during this study as was administered during BA058-05-003 (Section 6.1).

 

At Month 3, subjects will return to the clinic for medication resupply, subject
diary review and questioning as to their use of concomitant medications and the
occurrence of adverse events.

 

At the Month 6 visit ECG, and safety labs will be performed.  Vertebral
fractures will be determined clinically and via protocol directed x-ray
evaluation; non-vertebral fractures will be determined clinically.  In addition,
subjects will undergo a DXA of the hip and spine (and wrist, if the subject was
enrolled in the wrist DXA sub-study in Study BA058-05-003), and have samples
drawn for bone markers and anti-BA058 antibodies.  Procedures are to be
performed as described in Section 7.0, Appendix 14.1 and Appendix 14.2.

 

At Months 12 and 18, subjects will return to the clinic for medication resupply,
subject diary review and questioning as to their use of concomitant medications
and occurrence of adverse events.

 

At Month 24, subjects will return to the clinic and will undergo clinical and
radiologic fracture assessments and have DXA of the hip and spine (and wrist, if
the subject was enrolled in the wrist DXA sub-study in Study BA058-05-003).  Any
adverse event or clinical laboratory abnormality recorded at the Month 6 Visit
will be monitored until it has resolved, become chronic or stable.

 

4.0                         SELECTION OF STUDY POPULATION

 

4.1                               Number of Subjects

 

Subjects who completed 18 months of treatment with either BA058 Injection 80
µg/Placebo in Study BA058-05-003 will be given the opportunity to participate in
the Extension Study at all participating centers.  Based on randomization to the
BA058 Injection 80 µg/Placebo arms in Study BA058-05-003, up to 1,600 subjects
may be entered into this study.

 

The specific inclusion and exclusion criteria for enrolling subjects in this
study are presented below in Sections 4.2 and 4.3, respectively.  Exceptions to
these criteria should occur infrequently and should be discussed in advance and
approved by the Sponsor Medical Monitor.

 

4.2                               Inclusion Criteria

 

Subjects must meet all of the following criteria to be eligible to participate
in this study:

 

1.                                      The subject was enrolled, randomized to
BA058 Injection 80 µg/Placebo and completed 18-months of blinded treatment
within Study BA058-05-003.

 

2.                                      The subject is no more than 40 days from
Visit 9 in Study BA058-05-003.

 

3.                                      The subject has read, understood, and
signed the written informed consent form for the Extension Study.

 

4.3                        Exclusion Criteria

 

Subjects with any of the following characteristics are not eligible to
participate in the study:

 

25

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1.                                      Subjects who were withdrawn from Study
BA058-05-003 for any reason.

 

2.                                      Subjects who experienced a
treatment-related SAE during Study BA058-05-003.

 

4.4                               Withdrawal of Subjects from the Study

 

Subjects will be informed that they have the right to withdraw from the study at
any time for any reason without prejudice to their medical care.

 

Consistent with the prior protocol, BA058-05-003, the Investigator must withdraw
subjects from the study prior at any time in the study for the following
reasons:

 

·             Treatment-related SAEs;

 

·             Refusal of treatment;

 

·             Refusal or inability to complete study procedures;

 

·             Lost to follow-up.

 

The Investigator should exercise his/her best judgment and also has the right to
withdraw subjects from the study during the study for any of the following
reasons:

 

·             ECOG Grade 3 or 4 adverse events [Refer to Appendix14.3];

 

·             A complex of adverse events which, in the judgment of the
Investigator justifies treatment cessation;

 

·             Serious intercurrent illness;

 

·             Non-compliance;

 

·             Protocol violations;

 

·             Administrative reasons.

 

If a subject is withdrawn or discontinued from the study, the reason for
withdrawal is to be recorded in the source documents and on the case report
form.  All subjects withdrawn prior to completing the study should be encouraged
to complete the Month 6 or Month 24 Visit (depending on the length of time on
study) including any outstanding radiologic assessment or BMD assessment by DXA.

 

4.5                               Temporary Suspension of Treatment

 

The Investigator has the right to suspend treatment with alendronate without
withdrawal of the subject from the study.  Reasons for temporary suspension of
treatment may include a medical reason unrelated to an adverse event (e.g., a
planned procedure), or important social or administrative events.  The reason
for the suspension of treatment is to be documented in the electronic case
report form (eCRF) and in source documents.

 

When treatment with alendronate is restarted, the subject should resume
treatment with the next scheduled dose (as if treatment had not been
interrupted).

 

4.6                               Replacement of Subjects

 

Subjects who have been enrolled into the study and subsequently withdraw or drop
out of the study will not be replaced.

 

26

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5.0                               STUDY TREATMENTS

 

5.1                               Study Medications

 

Alendronate will be sourced locally.  Calcium and vitamin D will be provided by
the study centers, similar to their provision in Study BA058-05-003.

 

5.1.1                     Alendronate

 

Alendronate will be sourced centrally for Europe, Hong Kong and the US, and will
be sourced locally for South America at the expense of the Sponsor.

 

Subjects will receive total weekly dose of oral alendronate at a dose of 70 mg
once per week beginning on Day 2 for 24 months.  Additional provisions for
dosing of alendronate should be followed based on the prescribing information. 
Alendronate provided will be in the approved, marketed formulation.  The
alendronate may be generic substitutable approved versions which contain
different inactive ingredients, but the amount of active free alendronate must
be equivalent to 70 mg per week.

 

5.1.1.1           Restrictions on Alendronate Use

 

Subjects should not receive alendronate if they have the following
conditions/limitations:

 

·                                          Abnormalities of the esophagus and
other factors which delay espophageal emptying such as stricture or achalasia.

 

·                                          Inability to stand or sit upright for
at least 30 minutes.

 

·                                          Hypocalcemia.

 

·                                          Known history of hypersensitivity to
alendronate, alendronate excipients, or related compounds.

 

5.1.2                     Calcium and Vitamin D Supplements

 

Calcium and vitamin D supplements will be sourced locally and provided by the
sites at the expense of the Sponsor.

 

5.2                               Packaging, Labeling and Storage

 

Centrally supplied alendronate will not be repackaged for the study, but will be
over-labeled according to local regulatory requirements as necessary.

 

Calcium and vitamin D supplements will not be relabeled for the study.

 

5.2.1                     Storage

 

Alendronate must be kept in a secure, limited-access storage area until
dispensed for use to a study subject.  Alendronate sodium should be stored in
the container provided at room temperature, 15-30ºC (59-86ºF).

 

Calcium and vitamin D supplements may be stored at room temperature.

 

5.3                               Treatment Assignment

 

All subjects who participate will continue to be identified by the same 7-digit
subject number that was assigned upon enrollment into Study BA058-05-003
throughout the study and on the eCRF.

 

27

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5.4                               Study Medication Administration

 

5.4.1                     Alendronate Administration

 

Alendronate must be taken with water only (not mineral water) at least 30
minutes before the first food, beverage or medicinal product (including
antacids, calcium supplements and vitamins) of the day.  Other beverages
(including mineral water), food and some medicinal products are likely to reduce
the absorption of alendronate.

 

The following instructions should be followed exactly in order to minimize the
risk of esophageal irritation and related adverse reactions.

 

·                  Alendronate should only be swallowed after getting up for the
day with a full glass of water (not less than 200 mL or 7 fl. oz.).

·                  Subjects should only swallow alendronate whole.  Subjects
should not crush or chew the tablet or allow the tablet to dissolve in their
mouths because of a potential for oropharyngeal ulceration.

·                  Subjects should not lie down until after their first food of
the day.

·                  Subjects should not lie down for at least 30 minutes after
taking alendronate.

·                  Alendronate should not be taken at bedtime or before arising
for the day.

 

At the Month 3, Month 6, Month 12 and Month 18 visits, the unused alendronate
tablets are to be returned to the clinic for counting and the subject will be
dispensed additional alendronate.  At the Month 24 visit, all unused alendronate
tablets are to be returned to the study site.

 

5.5                               Treatment Compliance

 

The study site personnel will perform drug accountability at each clinic visit
and review each subject diary (refer to Section 7.1.16).  Accountability will be
documented on the appropriate forms and subjects will be re-trained on
administration as appropriate.  All doses of study medication are to be
self-administered.

 

If a subject does not administer or take all study medication including vitamin
D or calcium, the reason for the missed dosing is to be recorded in source
documents and on the eCRF.

 

Returned, unused alendronate will be accounted for by the study site and
destroyed as appropriate.

 

5.6                               Unblinding of Study Medication

 

Not applicable.

 

6.0                         CONCOMITANT MEDICATIONS

 

6.1                               Concomitant Medications

 

Vitamin D and calcium supplements are required to be administered daily from Day
1 (continuing from Protocol BA058-05-003) until the Month 6 Visit.  Vitamin D
and calcium supplements will be administered in the following doses: 400-800
IU/day (Vitamin D) and 500-100mg/day (calcium), or at a dose to be determined by
the Investigator and agreed upon by the Sponsor Medical Monitor according to the
subjects need.  The doses and schedule of Vitamin D and calcium supplements,
which are part of the study medication protocol, should

 

28

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be adhered to and not be changed other than for medical necessity.  The
supplements should be taken in the evening with or without food or as otherwise
instructed by the Investigator.

 

For any required concomitant medication, such as statins or antihypertensives,
the subject must be on a stable dose at study entry and every effort should be
made to maintain a stable dose during study participation.

 

The occasional use of over-the-counter medications at approved doses (e.g.,
ibuprofen or acetaminophen) for headache or minor discomfort is allowed. 
Occasional short term (<3 months) use of corticosteroids for seasonal allergies
or asthma is also allowed.  These are to be recorded on the appropriate case
report form.  Subjects should not take any other medications, including
over-the-counter medications, herbal medications, or mega-doses of vitamins
during the study without prior approval of the Investigator.

 

If it becomes necessary for a subject to take any other medication during the
study, the specific medication(s) and indication(s) must be discussed with the
Investigator.  All concomitant medications taken during the course of the study
must be recorded in the Subject’s medical record or source document and
transcribed into the case report form.

 

6.2                               Prohibited Medications

 

Subjects who require treatment during the course of the study with either an
anticonvulsant (phenobarbital, phenytoin, carbamazepin or primidone) or chronic
treatment with any form of heparin will be discontinued.  Estrogens given as HRT
are allowed at entry into the study but cannot be initiated during the study
except for local low dose vaginal estrogen.

 

Drugs that may compromise renal function such as non-steroidal anti-inflammatory
drugs should be used with caution.

 

7.0                               STUDY ASSESSMENTS

 

Subjects randomized to BA058 Injection 80 µg/Placebo in Study BA058-05-003 will
receive alendronate at a dose of 70 mg once per week for a total of 24 months.

 

The assessments performed at each study visit are displayed in the Schedule of
Visits and Procedures in Appendix 14.1.  Appendix 14.2 provides a more detailed
schedule of the study procedures by study visit with a suggested order of
procedure conduct.  Exact procedures for centrifuging, storage, and shipping of
laboratory samples will be detailed in a separate document.  The actual time of
each blood collection will be recorded on the appropriate source documents and
in the eCRF.

 

Study-specific assessments are to be conducted only after the subject has
provided written informed consent to participate in this study.  The study
assessments are described in more detail in Section 7.1 below.

 

7.1                               Clinical Procedures/Assessments

 

7.1.1                     Informed Consent

 

At the End-of-Treatment Visit (Visit 9) for Study BA058-05-003, the possibility
of participating in the Extension Study will be discussed with the subjects
randomized to BA058 80 µg/Placebo.  The Informed Consent must be signed prior to
undergoing any

 

29

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BA058-05-005 study related procedures, and may be signed at either Visit 9 or
Visit 10 of Study BA058-05-003.

 

7.1.2                     Recent Health Status

 

The subject’s health status will be updated from their last visit in Study
BA058-05-003, as necessary.  Any changes in health status should be recorded as
an adverse event, as appropriate.

 

The physical examination from the End-of-Treatment visit (Visit 9) of Study
BA058-05-003 will be the baseline for this study (Day 1).

 

Interim or symptom-directed physical examinations may be performed at the
discretion of the Investigator, if necessary, to evaluate adverse events or
clinical laboratory abnormalities.

 

7.1.3                     Vital Signs

 

Blood pressure, body temperature (ºC), pulse (bpm) and respiration rate (breaths
per minute) are to be measured and recorded at each study visit (Day 1, Month 3
and Month 6, Month 12, Month 18 and Month 24).  Only the Day 1 blood pressure
assessments need be conducted as an orthostatic measurement (See Section 7.1.5).

 

7.1.4                     Height and Weight

 

Height and weight are to be measured at each study visit (Day 1, Month 3, Month
12, Month 18 and Month 24).  Height is to be measured in the standing position
using a medical stadiometer.

 

7.1.5                     Orthostatic Blood Pressure and Heart Rate

 

The Day 1 orthostatic blood pressure measurement for Study BA058-05-005 will
serve as the Visit 10 orthostatic blood pressure for Study BA058-05-003.  Blood
pressure (mmHg; measured in the same arm at each visit) and pulse rate (bpm)
will be measured after five minutes in the supine position.  Immediately
following this measurement, blood pressure will be measured again after three
minutes in the standing position.

 

7.1.6                     Electrocardiogram

 

A twelve-lead supine electrocardiograms (ECGs) will be performed and the
following ECG parameters will be recorded: rhythm, heart rate, PR interval, QRS
duration and QT/QTc.

 

The Day 1 ECG measurement for Study BA058-05-005 will serve as the Visit 10 ECG
measurement for Study BA058-05-003.  An ECG will also be obtained at Month 6.

 

7.1.7                     Clinical Laboratory Evaluations

 

Clinical laboratory evaluations will be performed by a central laboratory. 
Prior to starting the study, the Sponsor (or its designee) will provide each
Investigator with copies of the appropriate laboratory certifications and normal
ranges for all laboratory parameters to be performed by that laboratory.

 

The blood and urinalysis samples are to be obtained under fasting conditions
(NPO for 8 hours; water is acceptable) in the morning of each scheduled study
visits on Day 1 and Month 6.

 

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All clinically significant laboratory abnormities indicating an adverse event
will be followed up by repeat testing and further investigated as necessary,
according to the judgment of the Investigator.

 

7.1.8                     Clinical Chemistry and Urinalysis (Dipstick)

 

Clinical chemistry and dipstick urinalysis will be performed on Day 1 and at
Month 6.  Urinalysis will be performed using samples freshly voided during the
clinic visit.  If there are positive findings noted on the dipstick, a urine
microscopic examination will be performed.  The following tests will be
performed:

 

Serum Chemistry

·

Sodium

 

·

Potassium

 

·

Chloride

 

·

Inorganic phosphorus

 

·

Albumin

 

·

Total protein

 

·

Glucose

 

·

Blood urea nitrogen (BUN)

 

·

Creatinine

 

·

Uric acid

 

·

Aspartate aminotransferase (AST)

 

·

Alanine aminotransferase (ALT)

 

·

Gamma-glutamyltranspeptidase (GGT)

 

·

Creatine phosphokinase (CPK)

 

·

Alkaline phosphatase

 

·

Total bilirubin

 

·

Lactate dehydrogenase (LDH)

 

·

Cholesterol

 

·

Triglycerides

 

·

Total calcium

Urinalysis

·

pH

 

·

Glucose

 

·

Protein

 

·

Ketones

 

·

Bilirubin

 

·

Blood

 

·

Urobilinogen

 

·

Specific gravity

 

·

Nitrite

 

·

Leukocytes

 

7.1.9                     Hematology

 

Hematology testing will be performed on Day 1 and at Month 6. The following
tests will be performed:

 

Hematology:

·

Hemoglobin

 

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·

Hematocrit

 

·

WBC count with differential in absolute counts

 

·

RBC count

 

·

Mean corpuscular volume (MCV)

 

·

Mean corpuscular hemoglobin concentration (MCHC)

 

·

Mean corpuscular hemoglobin (MCH)

 

·

Platelet count

 

7.1.10              Coagulation

 

Coagulation testing will be performed on Day 1 and at Month 6. The following
tests will be performed:

 

 

·

Prothrombin time (PT)

 

·

Partial thromboplastin time (PTT)

 

7.1.11              24-Hour Urine Collection

 

The 24-hour urine collection is to be begun the day before the Day 1 and Month 6
visits.  If a sample was not able to be collected on the day prior to the Day 1
visit (i.e., if the subject had not yet signed the ICF for study participation),
a 24-hour urine sample must be collected on the day prior to the Month 3 visit. 
Subjects are to be instructed to begin the urine collection by discarding the
first morning void (~6 a.m.) the day prior to the scheduled clinic visit and to
then collect their urine for 24 hours.  A final void is to be collected at the
end of the 24-hour period and the urine collection transported to the clinic by
the subject.  The 24-hour urinalysis will be used to measure urinary calcium and
urinary creatinine.

 

7.1.12              Bone Mineral Density

 

All subjects will have bone mineral density measurements (BMD) taken via DXA at
Month 6 and at Month 24.  The End-of-Treatment (Visit 9) bone mineral density
tests for Study BA058-05-003 will serve as the baseline BMD measurements for
Study BA058-05-005.

 

DXAs will be performed on the hip (femoral neck) and spine (L1-4).  The spinal
DXA is to be taken in the postero-anterior (PA) projection with any subsequent
spinal DXA to be taken in the same projection.  Subjects who underwent wrist
DXAs in Study BA058-05-003 will also have wrist DXAs performed at Month 6 and
Month 24.  The same side of the hip and wrist that were used in Study
BA058-05-003 must be used for the DXA scan, and the same scanner should be used
throughout the study, when possible.

 

7.1.13              Serum Markers of Bone Metabolism

 

Blood samples to measure bone markers will be taken on Day 1 and at Month 6. 
The results of the bone markers will be reported in the same subset of subjects
reported on for Study BA058-05-003.

 

The following markers of bone formation will be measured:

 

·                  Serum N-terminal propeptide of type I procollagen (PINP);

 

·                  Serum bone-specific alkaline phosphatase (BSAP);

 

·                  Serum osteocalcin.

 

The following marker of bone resorption will be measured:

 

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·                  Serum C-telopeptides of type 1 collagen crosslinks (CTX).

 

7.1.14              Clinical and Radiologic Evaluation of Fractures

 

Subjects will undergo protocol directed antero-posterior and lateral radiographs
of the lumbar and thoracic spines at Month 6 and Month 24.  The End-of-Treatment
(Visit 9) clinical and radiological evaluation of fractures for Study
BA058-05-003 will serve as the baseline assessments for Study BA058-05-005. 
Subjects will also be clinically evaluated for non-vertebral fractures (wrist,
hip, rib, etc.) that occur de novo during the Treatment Period.

 

All radiographs will be viewed and assessed centrally by a blinded, independent
assessor (radiologist) on the basis of existing baseline and study-acquired
vertebral deformity.  Fractures will be assessed according to the severity scale
of Genant (1993).  A second blinded radiologist will confirm the assessment of
the first reviewer for all subject radiographs in which an incident fracture has
been identified.  In the case of any disagreement, a third consensus assessment
will be made to adjudicate the incident fracture.

 

Fractures identified during the study will not be recorded as AEs unless the
subject is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the subject’s underlying
osteoporosis.  All fractures (vertebral and non-vertebral) will be identified
and evaluated as part of the disease assessment and will be documented in the
case report forms and source documents.

 

7.1.15              BA058 Antibody Assessments

 

The occurrence of anti-drug antibodies will be assessed at the completion of the
initial six months of the study.  Serum samples will be drawn at Month 6.  Any
subject who tests positive, or has previously tested positive for antibodies
subjects will be retested at six month intervals under a separate Safety
Surveillance protocol.  Exact procedures for collection, preparation, storage,
and shipping of these samples will be detailed in a separate document.  The
actual time and date of each blood collection will be recorded on the
appropriate source document and in the eCRF.

 

7.1.16              Subject Diaries

 

A weekly diary will be completed by the subject beginning on the Day 1 visit and
continuing until the last day of Month 24.  This diary will capture missed doses
of vitamin D, calcium and alendronate.  The weekly diary will be reviewed at
each study visit.

 

7.1.17              Activity and Diet

 

Subjects who qualify for enrollment in the study will have no restrictions
placed on their usual level of activity or on their usual diet, unless directed
by the treating physician for medically justified reasons.

 

8.0                         ADVERSE EVENTS AND SAFETY EVALUATION

 

Timely, accurate, and complete reporting and analysis of safety information from
clinical studies are crucial for the protection of subjects, Investigators and
the Sponsor, and is mandated by Regulatory Agencies worldwide.  All clinical
trials sponsored by RADIUS will be conducted in accordance with Standard
Operating Procedures (SOPs) that have been established to conform to regulatory
requirements worldwide to ensure appropriate reporting of safety information.

 

33

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8.1                         Definitions, Documentation, and Reporting

 

8.1.1                     Adverse Event Definition

 

An adverse event (AE) is any untoward medical occurrence in a subject
administered a pharmaceutical product, which does not necessarily have a causal
relationship with the treatment.  An AE can be any unfavorable and unintended
sign (including an abnormal laboratory finding), symptom, or disease temporally
associated with the use of the study drug, whether or not it is considered to be
study drug related.  This includes any newly occurring event or previous
condition that has increased in severity or frequency since the administration
of study drug.

 

8.1.2                     Serious Adverse Event Definition

 

A serious adverse event (SAE) is any adverse event, occurring at any dose and
regardless of causality that:

 

·                  Results in death.

 

·                  Is life-threatening.  Life-threatening means that the subject
was at immediate risk of death from the reaction as it occurred, i.e., it does
not include a reaction which hypothetically might have caused death had it
occurred in a more severe form.

 

·                  Requires in-patient hospitalization or prolongation of
existing hospitalization.  Hospitalization admissions and/or surgical operations
scheduled to occur during the study period, but planned prior to study entry are
not considered AEs if the illness or disease existed before the subject was
enrolled in the trial.  Provided that the illness/disease did not deteriorate in
an unexpected manner during the trial (e.g., surgery performed earlier than
planned).

 

·                  Results in persistent or significant disability/incapacity. 
Disability is defined as a substantial disruption of a person’s ability to
conduct normal life functions.

 

·                  Is a congenital anomaly/birth defect.  This includes any
anomaly detected at or after birth, or any anomaly that results in fetal loss.

 

·                  Is an important medical event.  An important medical event is
an event that may not result in death, be life-threatening, or require
hospitalization, but may be considered an SAE when, based upon appropriate
medical judgment, it may jeopardize the subject and may require medical or
surgical intervention to prevent one of the outcomes listed in the definitions
for SAEs.  Examples of such medical events include allergic bronchospasm
requiring intensive treatment in an emergency room or at home, blood dyscrasias
or convulsions that do not result in in-patient hospitalization, or the
development of drug dependency or drug abuse.

 

Clarification should be made between the terms “serious” and “severe” since they
are not synonymous.  The term “severe” is often used to describe the intensity
(synonym: severity) of a specific event (as in mild, moderate, or severe
myocardial infarction); the event itself, however, may be of relatively minor
medical significance (such as a severe headache).  This is not the same as
“serious,” which is based on subject/event outcome or action criteria described
above and are usually associated with events that pose a threat to a subject’s
life or functioning.  A severe adverse event does not necessarily need to be
considered serious.  For example, persistent nausea of several hours duration
may be considered severe nausea but not

 

34

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an SAE.  On the other hand, a stroke resulting in only a minor degree of
disability may be considered mild, but would be defined as an SAE based on the
above noted criteria.  Seriousness (not severity) serves as a guide for defining
regulatory reporting obligations.

 

8.2                         Monitoring of Adverse Events and Period of
Observation

 

All AEs will be monitored until they are resolved or have become chronic or
stable.  AEs and SAEs will be recorded on the case report forms starting from
the time of subject entry from Day 1 of the study until the final study visit
(Month 24).  Any SAEs that occur at any time after completion of the study,
which the Investigator considers to be related to study drug, must be reported
to the Sponsor or its designee.

 

8.3                         Procedures for Recording and Reporting AEs and SAEs

 

All adverse events spontaneously reported by the subject and/or in response to
an open question from study personnel or revealed by observation, physical
examination or other diagnostic procedures must be recorded in the source
document and on the appropriate page of the case report form.  Any clinically
relevant deterioration in laboratory assessments or other clinical findings is
considered an adverse event and must be recorded on the appropriate pages of the
case report form.  When possible, signs and symptoms indicating a common
underlying pathology should be noted as one comprehensive event.

 

All SAEs that occur during the course of the study, as defined by the protocol,
must be reported by the Investigator to the Study Safety Officer by completing
and transmitting the SAE Form within one working day from the point in time when
the Investigator becomes aware of the SAE.  In addition, all SAEs including all
deaths, which occur up to and including 30 days after administration of the last
dose of study drug, must be reported to the Study Safety Officer within one
working day.  All SAEs and deaths must be reported whether or not considered
causally related to the study drug.  SAE forms will be provided to the study
site.  The information collected will include a minimum of the following:
Subject number, a narrative description of the event, and an assessment by the
Investigator as to the intensity of the event, and relatedness to study drug. 
Follow-up information on the SAE may be requested by the CRO, the Study Safety
Officer or the Sponsor Medical Monitor.  Contact information for reporting SAEs
to the Study Safety Officer is provided on the SAE form.

 

It is the responsibility of the Investigator to promptly notify the
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) of all
serious adverse drug reactions involving risk to human subjects in accordance
with the requirements of the IRB/IEC.  An unexpected event is one that is not
reported in the Investigator’s Brochure.

 

Planned hospital admissions or surgical procedures for an illness or disease
that existed before the subject was enrolled in the trial or before study drug
was given are not to be considered AEs unless they occur at a time other than
the planned date.

 

Fractures identified during the study are not to be recorded as AEs unless the
subject is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the subject’s underlying
osteoporosis.  All fractures will be identified and evaluated as part of the
disease assessment and will be documented in the case report forms and source
documents.

 

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For both serious and non-serious adverse events, the Investigator must determine
the intensity of the event and the relationship of the event to study drug
administration.  Intensity for each AE will be defined according to the
following criteria:

 

Intensity

 

Definition

Mild

 

Awareness of sign or symptom, but easily tolerated.

Moderate

 

Discomfort enough to cause interference with normal daily activities.

Severe

 

Inability to perform normal daily activities

 

If the intensity of an adverse event changes within a day, the maximum intensity
should be recorded.  If the intensity changes over a longer period of time, the
changes should be recorded as separate events (having separate onset and stop
dates for each intensity).

 

Relationship to study drug administration will be determined by the Investigator
according to the following criteria:

 

Relationship

 

Definition

None

 

No relationship between the event and the administration of study drug. The
event is related to other etiologies, such as concomitant medications or
subject’s clinical state.

Unlikely

 

The current state of knowledge indicates that a relationship to study drug is
unlikely or the temporal relationship is such that study drug would not have had
any reasonable association with the observed event.

Possible

 

A reaction that follows a plausible temporal sequence from administration of the
study drug and follows a known response pattern to the suspected study drug. The
reaction might have been produced by the subject’s clinical state or other modes
of therapy administered to the subject.

Probable

 

A reaction that follows a plausible temporal sequence from administration of the
study drug and follows a known response pattern to the suspected study drug. The
reaction cannot be reasonably explained by the known characteristics of the
subject’s clinical state or other modes of therapy administered to the subject.

 

For the purpose of safety analyses, all AEs that are classified with a
relationship to study medication administration of possible or probable will be
considered treatment-related events.

 

8.4                         Rules for Suspension of the Study

 

As this is an extension study using standard-of-care management of osteoporosis,
including products approved for treatment, it is not anticipated that the study
will need to be suspended, and therefore, suspension rules are not assigned.  In
the event that the prior study (Study BA058-05-003) is suspended, the
circumstances of the Study BA058-05-003 suspension will be considered to
determine if this study, Study BA058-05-005, should be suspended as well.

 

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9.0                         STATISTICAL PROCEDURES

 

The primary objective of this study is to evaluate data obtained following six
months of standard-of-care osteoporosis treatment, including treatment with
alendronate, in subjects who have previously received 18 months of blinded
treatment with BA058 Injection 80 µg/Placebo.  Safety data will be obtained with
clinical, laboratory and radiologic assessment.  Following the initial six
months of treatment in this study, subjects will then enter the long-term
observational phase of this study during which the subjects will continue to
receive alendronate treatment for an additional 18 months.

 

The specific objectives of this study are to:

 

·                  Provide additional information on safety in study subjects
receiving six months of treatment with alendronate following 18 months of
treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide information on the vertebral fracture rate of
subjects receiving six months of treatment with alendronate following 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on non-vertebral fractures and
BMD change associated with six months of treatment with alendronate following 18
months of treatment with BA058 Injection 80 µg/Placebo.

 

·                  Provide additional information on BMD change and osteoporosis
status associated with 24 months of treatment with alendronate after 18 months
of treatment with BA058 Injection 80 µg/Placebo.

 

The analysis performed at six months will be used as a follow-up to the 18 month
fracture endpoint for Study BA058-05-003.  Additional analyses performed on data
in this study will be descriptive in nature.  Full details of the statistical
procedures to be used will be provided in the Statistical Analysis Plan.

 

9.1                         Sample Size

 

As this is an extension study, no formal sample size analysis was performed for
this study.  Study data will be tabulated and summarized.

 

9.2                         Randomization, Stratification and Blinding

 

Osteoporosis treatment will be open label and no randomization is required.

 

9.3                         Populations for Analysis

 

All analyses and data summaries will be presented for the Safety Population.

 

9.3.1                     Safety Population

 

The Safety Population is comprised of all subjects who qualify on the basis of
Study BA058-05-003 and provide informed consent to enroll in this Extension
Study.

 

9.4                         Procedures for Handling Missing, Unused, and
Spurious Data

 

All available data will be included in the data listings and tabulations. Where
appropriate, imputations of values for missing data will be performed using last
observation carried

 

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forward and specified in the Statistical Analysis Plan.  All data recorded on
the CRF will be included in the data listings that will accompany the clinical
study report.

 

9.5                         Statistical Methods

 

9.5.1                     Statistical Considerations

 

Statistical analysis will focus on longer term safety, fracture incidence,
including vertebral fracture and BMD change following six months of
standard-of-care osteoporosis treatment in subjects who have previously received
18 months of blinded treatment with BA058 Injection 80 µg/Placebo.  The analyses
will be performed based on the treatment arm they were randomized to in the
BA058-05-003 study.  The analyses performed on data collected at Month 12 and
Month 24 will be descriptive in nature and will be summarized descriptively with
number, percentage (for categorical variables), mean, standard deviation,
median, minimum and maximum (for continuous variables).

 

The analyses performed at six months will be used as a follow-up to the 18 month
fracture endpoint for Study BA058-05-003.  At this time-point, subjects will be
analyzed based upon the randomization assignment in the BA058-05-003 study.

 

9.5.2                     Baseline Comparisons

 

Baseline characteristics, medical history, physical examination, vital signs and
ECG, will be summarized using standard descriptive statistics.

 

9.5.3                     Fractures and BMD Analysis

 

All specified endpoints will be summarized by treatment group and study period
using standard descriptive statistics (n, mean, SD, median, minimum, maximum, or
n and %, as appropriate).  The fracture incidence and BMD results from the
additional six months of treatment with alendronate will be tabulated based on
the treatment arm they were randomized to in the BA058-05-003 study, with
additional tabular categories for results from the entire contiguous 24 months
from the baseline of Study BA058-05-003, for subjects who eventually enter study
BA058-05-005.  These descriptive analyses will be conducted on all subjects with
baseline and post-baseline data.  The analysis performed at six months will be
used a follow-up to the 18 month fracture endpoint for Study BA058-05-003.  The
data collected at Month 12 and Month 24 will be tabulated for each efficacy
endpoint (vertebral fracture, non-vertebral fracture, and spine, femoral neck
and forearm BMD).  This information will be summarized according to original
treatment assignment, osteoporosis medications taken between Month 6 and Month
24, and other patient characteristics.

 

9.5.4                     Safety Analysis

 

Data will be summarized and tabulated based on the enrolled population for this
Extension Study.  All subjects enrolled in the Extension Study will be included
in the safety analysis that will be performed on the following parameters:

 

·                  Incidence and severity of AEs;

 

·                  Pathological changes in hematology, chemistry and urinalysis
data based on normal ranges supplied by the clinical laboratory, if applicable;

 

Safety assessments for changes in physical examination, vital signs, ECG, and
laboratory tests will be descriptively summarized by treatment and study
periods.  The results of anti-

 

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BA058 testing will be summarized.  Concomitant medication classes will be
categorized using World Health Organization (WHO) drug dictionary and summarized
by number and percent of subjects using each class by treatment group.  All
treatment emergent adverse events (TEAEs) will be coded for system organ class
(SOC) and preferred term (PT) using MedDRA and the number (%) of subjects
experiencing each AE (SOC/PT) will be summarized by treatment, relationship to
treatment, and severity.  All serious adverse events (SAE) will be listed and
the number (%) of subjects with an SAE presented by treatment group.

 

9.5.5                     Procedures for Reporting Deviations to Original
Statistical Analysis Plan

 

All deviations from the original statistical analysis plan will be provided in
the final clinical study report.

 

9.6                         Data Oversight

 

9.6.1                     Central Review of Radiographs and DXA Scans

 

All radiographs will be viewed and assessed by a blinded, independent assessor
(radiologist) on the basis of existing baseline and study-acquired vertebral
deformity, and fractures will be assessed according to the method of Genant.  A
second blinded radiologist will review the assessment of the first reviewer for
all subject radiographs in which an incident fracture has been identified.  In
the case of any disagreement, a third consensus assessment will be made to
adjudicate the incident fracture.  All study DXA scans will also be evaluated
centrally by a blinded independent reviewer.  The primary objective of the
independent review is to provide objective data to determine the treatment
benefit as demonstrated on the pertinent radiologic and clinical data associated
with this study.

 

10.0                  ADMINISTRATIVE REQUIREMENTS

 

10.1                  Good Clinical Practice

 

This study will be conducted in accordance with the International Conference on
Harmonization (ICH) for Good Clinical Practice (GCP) and the appropriate
regulatory requirements.  The Investigator will be thoroughly familiar with the
appropriate use of the study medication as described in the protocol and the
Investigator’s Brochure.  Essential clinical documents will be maintained to
demonstrate the validity of the study and the integrity of the data collected. 
The Investigator/institution should establish master files at the beginning of
the study which will be maintained and updated during the study and retained
thereafter according to the appropriate regulations.

 

10.2                  Ethical Considerations

 

The study will be conducted in accordance with ethical principles founded in the
Declaration of Helsinki.  The Institutional Review Board (IRB)/Independent
Ethics Committee (IEC) will review all appropriate study documentation in order
to safeguard the rights, safety and well-being of the subjects.  The study can
only be conducted at study sites where IRB/IEC approval has been obtained.  The
protocol, informed consent form, Investigator’s Brochure, advertisements (if
applicable), and all other forms of information given to subjects will be
provided to the IRB/IEC by the Investigator.  In addition, reports on the
progress of the study will be submitted to the IRB/IEC by the Investigator at
the appropriate intervals.

 

39

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10.3                  Subject Information and Informed Consent

 

Each subject (or a legally authorized representative) must give written informed
consent prior to any new study-specific procedures being conducted.  It is the
responsibility of the Investigator to ensure written informed consent is
obtained from each subject participating in this study after an explanation of
the objectives, methods, discomforts and potential risks of the study has been
provided.  The Investigator (or study personnel) must also explain to each
subject that he/she is free to refuse participation in the study or to withdraw
from it at any time.  Each subject will also be told that his/her records may be
examined by competent authorities and authorized persons but that personal
information will be treated as strictly confidential and will not be publicly
available.

 

The informed consent form must be in accordance with the Declaration of
Helsinki, ICH and GCP guidelines, and be approved by the Sponsor and the
IRB/IEC.  State or local laws may require additional information.  Each subject
(or his/her legally authorized representative) must sign and be given a copy of
the informed consent form.  Each subject’s signed informed consent form must be
maintained by the Investigator and be readily available for review by the
Sponsor (or its designee) or the Regulatory Authorities.

 

10.4                  Protocol Compliance

 

The Investigator will conduct this study in compliance with the protocol
provided by the Sponsor and given approval/favorable opinion by the IRB/IEC and
the appropriate Regulatory Authority(ies).  Changes to the protocol will not be
made without agreement of the Sponsor Medical Monitor.  All changes to the
protocol will require IRB/IEC approval prior to implementation, except when
necessary to eliminate an immediate hazard to study subjects or when the change
involves only logistical or administrative aspects of the study (e.g., change in
Sponsor Medical Monitor or telephone number).  The IRB/IEC may provide, if
applicable regulations permit, expedited review and approval/favorable opinion
for minor changes in ongoing studies.  The Sponsor will submit all protocol
changes to the appropriate Regulatory Authority in accordance with the governing
regulations.

 

In situations requiring a departure from the protocol, the Investigator or other
physician in attendance will contact the Sponsor Medical Monitor by telephone,
e-mail or fax.  If possible, this contact will be made before implementing any
departure from the protocol.  In all cases, contact with the Sponsor Medical
Monitor must be made as soon as possible in order to review the situation and
agree on an appropriate course of action.  The case report form and source
document will describe any departure from the protocol and the circumstances
requiring it.

 

10.5           Case Report Form Completion

 

eCRFs will be developed to collect information obtained during this study.  It
is the Investigator’s responsibility to ensure that the e-CRFs are completed for
each subject enrolled in this study and for the accuracy, completeness,
legibility and timeliness of the data reported in each e-CRF.  Data for subjects
who are screened but not enrolled into the study because they do not meet study
criteria or do not complete all screening procedures, should be recorded in the
e-CRF.

 

eCRFs will be completed and any corrections of data will be made according to
procedures provided by the Sponsor (or designee).

 

40

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10.6                  Source Documents

 

Source documents are defined as original documents, data and records.  This may
include hospital records, clinical and office charts, laboratory
data/information, work sheets, subjects’ diaries or evaluation checklists,
pharmacy dispensing and other records, recorded data from automated instruments,
microfiches, photographic negatives, microfilm or magnetic media, ECG printouts,
and/or x-rays.

 

The Investigator(s)/institution(s) will permit trial-related monitoring,
audits, IRB/IEC review, and regulatory inspection(s), providing direct access to
source data documents.

 

10.7                  Study Monitoring

 

The Sponsor (or its designee) will ensure that the study is monitored in
accordance with ICH-GCP Guidelines.  Monitoring is the act of overseeing the
progress of a clinical trial and of ensuring that it is conducted, recorded, and
reported in accordance with the protocol, standard operating procedures, Good
Clinical Practice, and the applicable regulatory requirements and that the study
data are accurate, complete and verifiable from source data.  All study
documentation and other source data will be made available to the Sponsor (or
its designee), the IRB and to Regulatory Authorities for inspection upon
request.

 

10.8                  On-Site Audits

 

Representatives of the IRB or the Sponsor (or designee) may visit the study site
to carry out an audit of the study in compliance with regulatory guidelines and
company policy.  Such audits will require access to all study records including
source documents, CRFs, and other study documents.  Direct access to these study
records must be guaranteed by the Investigator, who must provide support for
these activities at all times.

 

Similar auditing procedures may also be conducted by agents of any Regulatory
Authority reviewing the results of this study.  The Investigator/institution
should immediately notify the Sponsor if they have been contacted by a
Regulatory Authority concerning an upcoming inspection.

 

10.9           Drug Accountability

 

Accountability for the study medication at the study site is the responsibility
of the Investigator.  Drug accountability will be performed only on alendronate,
calcium and vitamin D.  The Investigator will ensure that the study medication
is used only in accordance with this protocol.  Where allowed, the Investigator
may choose to assign some of the study medication accountability
responsibilities to qualified study personnel.

 

Study medication accountability records indicating the delivery date to the
study site, inventory at the study site and dispensing/use will be maintained. 
These records will adequately document that the study medications were dispensed
and returned as specified in the protocol.  Accountability records will include
dates, quantities, and subject numbers.  The Sponsor (or its designee) will
review study medication accountability records at the study site on an ongoing
basis during the study.  All used and unused study medication must be
inventoried, accounted for, and approved by the Sponsor (or its designee) prior
to destruction.  If the site is not capable of study drug disposal/destruction,
the Sponsor will arrange for an alternative method.  Records of disposal must be
maintained with the study records.

 

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10.10           Record Retention

 

The Investigator will maintain all study records according to ICH/GCP and
applicable regulatory requirements.  Essential documents must be retained for
two years after the final marketing approval in an ICH region or at least two
years have elapsed since the discontinuation of clinical development of the
study medication.  It is the responsibility of the Sponsor to inform the
Investigator of when these documents can be destroyed.  In addition, all subject
medical records and other source documentation will be kept for the maximum time
permitted by the hospital, institution or medical practice.

 

The Investigator/institution will take measures to prevent accidental or
premature destruction of these documents.  If the responsible Investigator
retires, relocates, or for other reasons withdraws from the responsibility of
keeping the study records, custody must be transferred to a person who will
accept the responsibility.  The Sponsor must be notified in writing of the name
and address of the new custodian.

 

10.11           Study Termination

 

This study may be terminated at any time by the Sponsor if there is sufficient
reasonable cause.  Circumstances that may warrant termination include, but are
not limited to:

 

·                  Determination of unexpected, significant, or unacceptable
risk to subjects.

 

·                  Failure of enrollment

 

·                  Administrative reasons

 

·                  Plans to modify, suspend or discontinue the development of
the study drug.

 

In addition, individual study sites may be terminated from study participation
for reasons including, but not limited to the following:

 

·                  Failure to enter subjects at an acceptable rate.

 

·                  Insufficient adherence to protocol requirements.

 

·                  Incomplete and/or non-evaluable data.

 

In all cases, the terminating parties will provide written notification
documenting the reason for study termination to all the relevant parties.

 

Should the study or an individual site be prematurely closed, all study
materials (completed, partially completed, and blank CRFs, study drug, etc.)
must be returned to the Sponsor (or its designee).

 

10.12           Liability and Insurance

 

The Sponsor has subscribed to an insurance policy covering, in its terms and
provisions, its legal liability for injuries caused to participating persons and
arising out of this research performed strictly in accordance with the
scientific protocol as well as with applicable law and professional standards.

 

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11.0                  USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

 

11.1                  Use of Information

 

All information regarding BA058 supplied by the Sponsor (or its designee) to the
Investigator is privileged and confidential information.  The Investigator
agrees to use this information to accomplish the study and will not use it for
other purposes without prior consent from the Sponsor.

 

The information developed during the conduct of this clinical study is also
considered confidential and will be used by the Sponsor in connection with the
development of BA058.  This information may be disclosed as deemed necessary by
the Sponsor to other clinical Investigators, other pharmaceutical companies, and
to Regulatory Authorities.  To allow for the use of the information derived from
this study and to ensure complete and thorough analysis, the Investigator is
obligated to provide the Sponsor (or its designee) with complete study results
and all data developed in this study and to allow direct access to source
data/documents for study-related monitoring, audits, IRB/IEC review, and
regulatory inspection.

 

11.2                        Publication

 

One publication of the study data is planned.  A Publications Committee composed
of Investigators participating in the study and representatives from the Sponsor
as appropriate will be formed to oversee the publication of the study results,
which will reflect the experience of all participating study centers.

 

Subsequently, individual Investigators may publish results from the study in
compliance with their agreement with the Sponsor.  A pre-publication manuscript
must be provided to the Sponsor at least 30 days prior to the submission of the
manuscript to a publisher.  Similarly, the Sponsor will provide any company
prepared manuscript to the Investigators for review at least 30 days prior to
submission to a publisher.

 

The Investigator shall comply with the policy of the Sponsor regarding
confidential or proprietary information in any such paper and agrees to withhold
publication of same for an additional 60 days in order to permit the Sponsor to
obtain patent or other proprietary rights protection, if the Sponsor deems it
necessary.

 

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12.0                        INVESTIGATOR AGREEMENT

 

To be completed by the Investigator

 

I have read Protocol BA058-05-005: “An Extension Study to Evaluate 24 Months of
Standard-of-Care Osteoporosis Management Following Completion of 18 Months of
BA058 or Placebo Treatment in Protocol BA058-05-003”.

 

I agree to conduct the study as detailed herein and in compliance with ICH
Guidelines for Good Clinical Practice and applicable regulatory requirements and
to inform all who assist me in the conduct of this study of their
responsibilities and obligations.

 

The signature below constitutes my agreement to the contents of this protocol.

 

 

 

 

 

Signature of Principal Investigator

 

Date

 

 

 

 

 

 

Principal Investigator (print)

 

 

 

 

Signature of Sponsor’s Medical Officer (where applicable)

 

 

 

 

 

Louis Brenner, MD

 

Date

 

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13.0                  REFERENCES

 

Balena R, Toolan BC, Shea M, Markatos A, Myers ER, Lee SC, Opas EE, Seedor JG,
Klein H, Frankenfield D, Quartuccio H, Fiovanti C, Clair J, Brown E, Hayes WC,
Rodan GA.  The effects of 2-year treatment with the aminobisphosphonate
alendronate on bone metabolism, bone histomorphometry, and bone strength in
ovariectomized nonhuman primates.  J Clin Invest 1993; 92:2577-2586.

 

Balena R, Markatos A, Seedor JG, Gentile M, Stark C, Peter CP, Rodan GA. 
Long-term safety of the aminobisphosphonate alendronate in adult dogs.  II
Histomorphometric analysis of the L5 vertebrae.  J Pharmacol Exp Ther 1996;
276(1):277-83.

 

Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF,
McGowan JA, Rosen CJ.  One year of alendronate after one year of parathyroid
hormone (1-84) for osteoporosis. N Engl J Med 2005; 353(6):555-565.

 

Bone HG, Hosking D, Devogelaer JP, Tucci JR, Emkey RD, Tonito RP,
Rodriguez-Portales JA, Downs RW, Grupta J, Santora AC, Liberman UA, Alendronate
Phase III Osteoporosis Treatment Study Group.  Ten years’ experience with
alendronate for osteoporosis in postmenopausal women.  N Eng J Med 2004;
350(12):1189-99.

 

Devogelaer JP, Broll H, Correa-Rotter R, Coming DC, De Deuxchaisnes CN, Geusens
P, Hosking D, Jaeger P, Kaufman JM, Leite M, Leon J, Liberman U, Menkes CJ,
Meunier PJ, Reid I, Rodriguez J, Romanowicz A, Seeman E, Vermeulen A, Hirsch LJ,
Lombardi A, Plezia K, Santora AC, Yates AJ, Yuan W.  Oral alendronate induces
progressive increases in bone mass of the spine, hip and total body over 3 years
in postmenopausal women with osteoporosis.  Bone 1996; 18(2):141-50.

 

EMEA. Guideline on the evaluation of medicinal products in the treatment of
primary osteoporosis. 2007.

 

FDA. Guidelines for preclinical and clinical evaluation of agents used in the
prevention or treatment of postmenopausal osteoporosis. 1994.

 

FDA. Draft guidance:  Development of parathyroid hormone for the prevention and
treatment of osteoporosis. 2000.

 

Fosamax® Prescribing Information.  Whitehouse Station, NJ: Merck Sharp & Dohme
Corp.; 2012.

 

Genant HK, Wu CY, van KC, and Nevitt MC. Vertebral fracture assessment using a
semiquantitative technique. J Bone Miner Res 1993; 8:1137-1148.

 

Guidance for Industry. E6 Good Clinical Practice: Consolidated Guidance.
U.S.Department of Health and Human Services, Food and Drug Administration.
April 1996.

 

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Gullberg B, Johnell O, Kanis JA.  World-wide projections for hip fracture. 
Osteoporos Int 1997; 7:407-413.

 

Lefage M-H, Balena R, Battle MA, Shea M, Seedor JG, Klein H, Hayes WC, Rodan
GA.  Comparison of alendronate and sodium fluoride effects on cencellous and
cortical bone in minipigs.  J Clin Invest 1995; 95:2127-2133.

 

Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J,
Downs Jr. RW, Dequeker J, Favus M, Seeman E, Recker RR, Capizzi T, Santora AC,
Lombardi A, Shah RV, Hirsch LJ, Karpe DB.  Effect of oral alendronate on bone
mineral density and the incidence of fractures in postmenopausal osteoporosis. 
N Engl J Med 1995; 333(22):1437-43.

 

Reginster JY, Burlet N.  Osteoporosis: still increasing prevalence.  Bone 2006;
38(Suppl 1):S4-9.

 

Rittmaster RS, Bolognese M, Ettinger MP, Hanley DA, Hodsman AB, Kendler DL,
Rosen CJ.  Enhancement of bone mass in osteoporotic women with parathyroid
hormone followed by alendronate.  J Clin Endocrinol Metab 2000; 85(6):2129-34.

 

Rizzoli R, Bonjour JP, and Ferrari SL. Osteoporosis, genetics and hormones. J
Mol Endocrinol 2001; 26:79-94.

 

Tucci JR, Tonino RP, Emkey RD, Peverly CA, Kher U, Santora AC 2nd.  Effect of
three years of oral alendroneate treatment in postmenopausal women with
osteoporosis. Am J Med 1996; 101(5):488-501.

 

WHO Scientific Group on the assessment of osteoporosis at primary health care
level.  World Health Organization Summary Meeting Report 2007.

 

World Medical Association Declaration of Helsinki. The World Medical
Association, Inc. 2008.

 

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14.0                                                APPENDICES

 

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Visit 1 2 3 4 5 6 Procedure Study Day/Month: Visit 10 003/ Visit 11 005 Month 3
Month 6 Month 12 Month 18 Month 24 Day 1 90 180 360 540 720 Visit Window (Days)
N/A ± 5 ± 14 ± 14 ± 14 ± 14 Informed consent X Review of entrance criteria X
Recent health status X X X X X X Vital signs, weight and height measurements2 X
X X X X X Electrocardiogram X X Urinalysis (dipstick) 3 X X Chemistry blood
collection4 X X Hematology blood collection5 X X Coagulation blood collection5 X
X PTH(1-84) X 25-hydroxy vitamin D level X 1,25-dihydroxy vitamin D level X
Serum markers of bone metabolism 5 X X BA058 antibody levels X 24-hour urine
collection (for calcium:creatinine and creatinine clearance)6 X X7 X Clinical
and radiologic (spine, lumbar and thoracic vertebrae) fracture X X assessments
Bone mineral density of hip and spine by DXA8 X X Bone mineral density of wrist
by DXA9 X X Calcium and vitamin D supplements Daily Alendronate administration
(if applicable) Dosing as per prescribing information Study medication resupply
(if applicable) X X X X Subject diary review10 X X X X X Document adverse events
and concomitant medications Daily

 

 

 

14.2                  Suggested Schedule of Events and Procedures by Study Visit

 

The purpose of this guide is to provide more detailed instructions for the study
procedures listed in Appendix 14.1.  This guide presents the procedures in a
suggested sequence of performance at each study visit.  Further information may
be found within the protocol and in other study reference manuals (e.g., ECG,
clinical laboratory sample processing).

 

Of note:

 

·                  Blood and urinalysis samples are to be obtained under fasting
conditions (NPO. for 8 hours; water is acceptable) in the morning of Day 1 and
Month 6.

 

·                  DXA Scans: Always use the same study-validated machine;
preferably the same technician.

 

·                  The 24-hour urine collection will be started at home the day
before the clinic visit where the collection is required.  Subjects will be
instructed to discard the first morning void and begin the collection at least
24 hours before their clinic visit the following day. They will collect all
urine for 24 hours with a final void before coming to the clinic. Routine
urinalyses are to be performed using samples freshly voided during the clinic
visit.  Subjects should receive a reminder to initiate their 24-hour urine 2
days before their scheduled visit.

 

·                  Alendronate for Europe, Hong Kong and the US will be sourced
centrally; alendronate for South America will be sourced locally by the medical
center and reimbursed by the Sponsor.

 

·                  Subjects will be instructed to take the calcium and vitamin D
supplements daily (in the evening with or without food or as otherwise
instructed by the Investigator) until discharge from the study.  This is
required until the end of Month 24.

 

49

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Definitions of Common Procedures:

 

The terms used in the by-visit schedule that follows are further defined below.

 

Recent health status (document any changes from last visit)

·                  Question subject regarding any new health issues

·                  Question subject regarding any new adverse events

·                  Question subject regarding any new concomitant medications

·                  Question subject regarding any new issues related to ability
to continue with study

Pulse, respiration and temperature:

·                  Pulse rate (beats/minute) taken after approximately five
minutes in the supine position.

·                  Respiration rate (breaths/minute).

·                  Body temperature (°C).

Weight and height measurements:

·                  Weight (kg).

·                  Height (cm) standing measurements are to be performed using
the same medical stadiometer and standardized procedures each time.

Orthostatic blood pressure:

·                  Orthostatic blood pressure (mmHg) (measured in same arm each
time/each visit) is measured after five minutes in the supine position followed
by a measurement taken after 3 minutes in the standing position.  Only the blood
pressure assessment on Day 1 (Visit 10) needs to be orthostatic.

ECG

·                  Twelve-lead supine electrocardiogram

·                  Print hard copy for reading by qualified study personnel

·                  More than one ECG may be performed per time-point.

24 hour urine collection

·                  Subject to discard first morning void (suggest 6 a.m.) on day
before clinic visit

·                  Subject to collect urine for approximately 24 hours

·                  Subject to collect final void at end of collection and bring
collection to clinic.

·                  Process for calcium and creatinine

Urinalysis

·                  Obtain under fasting conditions (NPO. except water for 8
hours)

·                  Routine urinalysis is to be performed using a sample freshly
voided during the clinic visit (microscopic examination if positive dipstick).

Review study medication administration procedures with subject

·                  Alendronate should be taken daily, preferably at the same
time each morning/day of the week

Scheduling and instructions for next clinic visit

·                  Schedule visit

·                  Remind subject of any fasting requirements

·                  Provide urine collection instructions and materials as
necessary

·                  Remind subjects to complete the diaries until the end of the
study

Vitamin D and calcium supplements

·                  Vitamin D and calcium supplements are required throughout the
study.  Only those supplements supplied as part of study medication may be used
and are to be used at the daily recommended dose (see Section 5.1.2).

·                  Supplements should be taken in the evening, with or without
food as instructed by the Investigator.

·                  At each study visit, assess the subject’s supply and resupply
as necessary.

·                  Drug usage reconciliation is to be performed when a new
supply is provided.

 

50

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Visit 10 for Study BA058-05-003

Day 1 Visit for Study BA058-05-005

Day 1

 

VISIT

 

ACTIVITIES

Day 1

 

Day 1 Visit for Study BA058-05-005

 

Visit 10 for Study BA058-05-003

 

Written informed consent must be obtained

Recent health status

·      Document any changes since End-of-Treatment visit (Visit 9) from Study
BA058-05-003

Study staff will receive your prior days 24-hour urine sample (if a 24-hour
urine sample was not collected prior to Day 1, the subject must begin a 24-hour
urine sample on the day prior to the Month 3 visit

Subject diary review

·      Review study medication diary (calcium and vitamin D)/dispense new diary
if necessary

·      Record deviations in dosing or any AEs in source documents and CRFs

·      Collect diaries and enter data into CRF

Vital signs, weight and height measurement

Orthostatic blood pressure

ECG

Blood collection:  fasting conditions (NPO except water for 8 hours)

·      Chemistry

·      Hematology

·      Coagulation (PT and PTT)

·      Serum markers of bone metabolism, where applicable

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

·      Urinalysis (Dipstick)

Study medication

·      Dispense three month supply of alendronate

·      Assess subject’s supply of calcium and vitamin D supplements; resupply as
necessary

·      Instruct subject to take daily until they are discharged from the study

Scheduling and instructions for next clinic visit

·      Remind subject to take study medication as instructed

·      24-hour urine collection:  If subjects did not provide a 24-hour urine
sample for Visit 1, dispense urine collection container and instruct subjects to
perform 24-hour urine collection beginning the morning 24 hours prior to their
next scheduled visit (Month 3)

·      Remind subject to record study medication use

               

51

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Month 3 Visit for Study BA058-05-005

Day 90 (±5 days)

 

VISIT

 

Activities

Month 3

 

Recent health status

·      Document any changes since previous visit

Study staff will receive the prior days 24 hour urine sample, if applicable

Vital signs, height and weight measurement

Subject diary review

·      Review study medication diary/dispense new diary if necessary

·      Record deviations in dosing or any AEs in source documents and CRFs.

·      Collect diaries and enter data into CRF

Study medication

·      Dispense three month supply of alendronate

·      Assess subject’s supply of calcium and vitamin D supplements; resupply as
necessary, instruct subject to take daily until they are discharged from the
study

Scheduling and instructions for next clinic visit

·      24-hour urine collection:  Dispense urine collection container and
instruct subjects to perform 24-hour urine collection beginning the morning 24
hours prior to their next scheduled visit (Month 6)

·      Remind subject to take study medication as instructed

·      Remind subject to record study medication use

 

52

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Month 6 Visit for Study BA058-05-005

Day 180 (±14 Days)

 

VISIT

 

Activities

Month 6

 

Physical Examination

Recent Health Status

·      Document any changes from last visit

Collect 24 hour urine sample from subject

Study staff will receive your prior days 24-hour urine sample

·      Review diary of study medication

·      Collect diary and enter data into CRF, record dosing deviations or any
AEs in source documents and CRFs

Vital signs, weight and height measurement

ECG

Blood collection:  fasting conditions (NPO except water for 8 hours)

·      Chemistry

·      Hematology

·      Coagulation (PT and PTT)

·      Serum markers of bone metabolism, where applicable

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

·      BA058 antibody levels

·      Urinalysis (Dipstick)

Clinical and radiologic fracture evaluations

·      Obtain antero-posterior and lateral radiographs of the lumbar and
thoracic vertebrae

·      Document any non-vertebral fractures

Bone mineral density

·      Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3
radius), where applicable.

Study Medication

·      Dispense six month supply of alendronate

·      Assess subject’s supply of calcium and vitamin D supplements, resupply as
necessary

Scheduling and instructions for next clinic visit

·      Remind subject to take study medication as instructed

·      Remind subject to record study medication use

 

53

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Month 12 Visit for Study BA058-05-005

Day 360 (±5 days)

 

VISIT

 

Activities

Month 12

 

Recent health status

·      Document any changes since previous visit

Vital signs, height and weight measurement

Subject diary review

·      Review study medication diary/dispense new diary if necessary

·      Record deviations in dosing or any AEs in source documents and CRFs.

·      Collect diaries and enter data into CRF

Study medication

·      Dispense six month supply of alendronate

·      Assess subject’s supply of calcium and vitamin D supplements; resupply as
necessary, instruct subject to take daily until they are discharged from the
study

Scheduling and instructions for next clinic visit

·      Remind subject to take study medication as instructed

·      Remind subject to record study medication use

 

54

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Month 18 Visit for Study BA058-05-005

Day 540 (±5 days)

 

VISIT

 

Activities

Month 18

 

Recent health status

·      Document any changes since previous visit

Vital signs, height and weight measurement

Subject diary review

·      Review study medication diary/dispense new diary if necessary

·      Record deviations in dosing or any AEs in source documents and CRFs.

·      Collect diaries and enter data into CRF

Study medication

·      Dispense six month supply of aalendronate

·      Assess subject’s supply of calcium and vitamin D supplements; resupply as
necessary, instruct subject to take daily until they are discharged from the
study

Scheduling and instructions for next clinic visit

·      Remind subject to take study medication as instructed

·      Remind subject to record study medication use

 

55

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Month 24 Visit for Study BA058-05-005

Day 720 (±5 days)

 

VISIT

 

Activities

Month 24

 

Recent health status

·      Document any changes since previous visit

Vital signs, height and weight measurement

Subject diary review

·      Review study medication diary

·      Record deviations in dosing or any AEs in source documents and CRFs.

·      Collect diaries and enter data into CRF

Clinical and radiologic fracture evaluations

·      Obtain antero-posterior and lateral radiographs of the lumbar and
thoracic vertebrae

·      Document any non-vertebral fractures

Bone mineral density

·      Perform DXA of spine (L1-L4), hip (femoral neck), and wrist (distal 1/3
radius), where applicable.

Study medication

·      Collect unused study medication

Discharge subject from study

·      Subject is terminated from the study unless adverse events require
further follow through

Discuss continuing treatment options

·      Subjects will receive standard-of-care management according to their
physician

 

56

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14.3      Eastern Cooperative Oncology Group (ECOG) Common Toxicity Criteria

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Haematology

 

 

 

 

 

 

 

 

 

 

WBC (x109/L)

 

4

 

3.0 - 3.9

 

2.0 - 2.9

 

1.0 - 1.9

 

< 1.0

Platelets (x109/L)

 

WNL

 

75.0 - normal

 

50.0 - 74.9

 

25.0 - 49.9

 

< 25.0

Haemoglobin (g/L);

(mmol/L)

 

WNL

 

100.0 - normal;

6.2 - normal

 

80.0 - 99.0;

5.0 - 6.1

 

65.0 - 79.0

4.0 - 4.9

 

< 65.0

< 4.0

Granulocytes/ Bands (x109/L)

 

2

 

1.5 - 1.9

 

1.0 - 1.4

 

0.5 - 0.9

 

< 0.5

Lymphocytes (x109/L)

 

2

 

1.5 - 1.9

 

1.0 - 1.4

 

0.5 - 0.9

 

< 0.5

Haemorrhage

 

none

 

mild, no transfusion

 

gross,
1 - 2 units transfusion per episode

 

gross,
3 - 4 units transfusion per episode

 

massive,
> 4 units transfusion per episode

Coagulation

 

 

 

 

 

 

 

 

 

 

Fibrinogen

 

WNL

 

0.99 - 0.75 x N

 

0.74 - 0.50 x N

 

0.49 - 0.25 x N

 

< 0.25 x N

Prothrombin time(quick)

 

WNL

 

1.01 - 1.25 x N

 

1.26 - 1.50 x N

 

1.51 - 2.00 x N

 

> 2.00 x N

Partial thromboplastin time

 

WNL

 

1.01 - 1.66 x N

 

1.67 - 2.33 x N

 

2.34 - 3.00 x N

 

> 3.00 x N

Metabolic

 

 

 

 

 

 

 

 

 

 

Hyperglycaemia (mmol/L)

 

< 6.4

 

6.4 - 8.9

 

9.0 - 13.9

 

14.0 - 27.8

 

> 27.8 or ketoacidosis

Hypoglycaemia (mmol/L)

 

> 3.6

 

3.6 - 3.1

 

3.0 - 2.3

 

2.2 - 1.7

 

< 1.7

Amylase

 

WNL

 

< 1.5 x N

 

1.5 - 2.0 x N

 

2.1 - 5.0 N

 

> 5.0 x N

Hypercalcaemia (mmol/L)

 

< 2.65

 

2.65 - 2.88

 

2.89 - 3.13

 

3.14 - 3.36

 

> 3.37

Hypocalcaemia (mmol/L)

 

> 2.10

 

2.10 - 1.94

 

1.93 - 1.74

 

1.73 - 1.52

 

< 1.51

Hypomagnesaemia (mmol/L)

 

> 0.58

 

0.58 - 0.48

 

0.47 - 0.36

 

0.35 - 0.24

 

< 0.23

Gastrointestinal

 

 

 

 

 

 

 

 

 

 

Nausea

 

none

 

able to eat reasonable intake

 

intake significantly decreased but can eat

 

no significant intake

 

—

Vomiting

 

none

 

1 episode
in 24 hrs

 

2 - 5 episodes
in 24 hrs

 

6 - 10 episodes
in 24 hrs

 

> 10 episodes in 24 hrs or requiring parenteral support

Diarrhoea

 

none

 

increase of 2 - 3 stools/day over pre-Rx

 

increase of 4 - 6 stools/day, or nocturnal stools, or moderate cramping

 

increase of 7 - 9 stools/day, or incontinence, or severe cramping

 

increase of > 10 stools/day or grossly bloody diarrhoea, or need for parenteral
support

Stomatitis

 

none

 

painless ulcers, erythema, or mild soreness

 

painful erythema, oedema, or ulcers but can eat solids

 

painful erythema, oedema, or ulcers and cannot eat solids

 

requires parenteral or enteral support for alimentation

Liver

 

 

 

 

 

 

 

 

 

 

Bilirubin (N = 17 µmol/L)

 

WNL

 

—

 

< 1.5 x N

 

1.5 - 3.0 x N

 

> 3.0 x N

Transaminase (SGOT, SGPT)

 

WNL

 

2.5 x N

 

2.6 - 5.0 x N

 

5.1 - 20.0 x N

 

> 20.0 x N

Alkaline phosphatase or 5-nucleotidase

 

WNL

 

< 2.5 x N

 

2.6 - 5.0 x N

 

5.1 - 20.0 x N

 

> 20.0 x N

 

57

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Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Liver- clinical

 

No change from baseline

 

—

 

—

 

precoma

 

hepatic coma

Kidney, bladder

 

 

 

 

 

 

 

 

 

 

Creatinine

 

WNL

 

< 1.5 x N

 

1.5 - 3.0 x N

 

3.1 - 6.0 x N

 

> 6.0 x N

Proteinuria

 

No change

 

1 (+) or
< 0.3 g% or 3 g/L

 

2 - 3 (+) or
0.3-1.0 g% or 3-10 g/L

 

4 (+) or
> 1.0 g% or > 10g/L

 

nephrotic syndrome

Haematuria

 

Negative

 

microscopic only

 

gross,
no clots no Rx needed

 

gross and clots
bladder irrigation

 

requires transfusion
or cystectomy

Weight gain/ loss

 

< 5.0 %

 

5.0 - 9.9 %

 

10.0 - 19.9 %

 

20.00%

 

—

Pulmonary

 

 

 

 

 

 

 

 

 

 

Pulmonary

 

none or no change

 

asymptomatic, with abnormality in PFTs

 

dyspnoea on significant exertion

 

dyspnoea at normal level of activity

 

dyspnoea at rest

Cardiac

 

 

 

 

 

 

 

 

 

 

Cardiac arrhythmias

 

none

 

asymptomatic, transient, requiring no therapy

 

recurrent or persistent, no therapy required

 

requires treatment

 

requires monitoring; or hypotension, or ventricular tachycardia or fibrillation

Cardiac function

 

none

 

asymptomatic, decline of resting ejection fraction by less than 20 % of baseline
value

 

asymptomatic, decline of resting ejection fraction by more than 20 % of baseline
value

 

mild CHF,
responsive to therapy

 

severe or
refractory CHF

Cardiac ischaemia

 

none

 

non-specific T- wave flattening

 

asymptomatic, ST and T wave changes suggesting ischaemia

 

angina without evidence of infraction

 

acute myocardial infarction

Cardiac- pericardial

 

none

 

asymptomatic effusion, no intervention required

 

pericarditis (rub, chest pain, ECG changes)

 

symptomatic effusion; drainage required

 

tamponade; drainage urgently required

Hypertension

 

none or no change

 

asymptomatic, transient increase by greater than 20 mmHg (D) or to > 150/100 if
previously WNL.
No treatment required.

 

recurrent or persistent increase by greater than 20 mmHG (D) or to > 150/100 if
previously WNL.
No treatment required.

 

requires therapy

 

hypertensive crisis

Hypotension

 

none or no change

 

changes requiring no therapy (including transient orthostatic hypotension)

 

requires fluid replacement or other therapy but not hospitalisation

 

requires therapy and hospitalisation; resolves within 48 hrs of stopping the
agent

 

requires therapy and hospitalisation for > 48 hrs after stopping the agent

Neurologic

 

 

 

 

 

 

 

 

 

 

Neuro: sensory

 

none or no change

 

mild paraesthesias;
loss of deep tendon reflexes

 

mild or moderate objective sensory loss moderate paraesthesias

 

severe objective sensory loss or paraesthesias that interfere with function

 

—

 

58

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Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Neuro: motor

 

none or no change

 

subjective weakness;
no objective findings

 

mild objective weakness without significant impairment of function

 

objective weakness with impairment of function

 

paralysis

Neuro: cortical

 

none

 

mild somnolence or agitation

 

moderate somnolence or agitation

 

severe somnolence, (>50 % waking hours), agitation, confusion, disorientation or
hallucinations

 

coma, seizures,
toxic psychosis

Neuro: cerebellar

 

none

 

slight incoordination, dysdiadochokinesia

 

intention tremor, dysmetria, slurred speech, nystagmus

 

locomotor ataxia

 

cerebellar necrosis

Neuro: mood

 

no change

 

mild anxiety or depression

 

moderate anxiety or depression

 

severe anxiety or depression

 

suicidal ideation

Neuro: headache

 

none

 

mild

 

moderate or severe
but transient

 

unrelenting and severe

 

—

Neuro: constipation

 

none or no change

 

mild

 

moderate

 

severe

 

ileus > 96 hrs

Neuro: hearing

 

none or no change

 

asymptomatic, hearing loss on audiometry only

 

tinnitus

 

hearing loss interfering with function but correctable with hearing aid

 

deafness not correctable

Neuro: vision

 

none or no change

 

—

 

—

 

symptomatic subtotal loss of vision

 

blindness

Pain

 

 

 

 

 

 

 

 

 

 

Pain

 

none

 

mild

 

moderate

 

severe

 

reg. narcotics

Skin

 

 

 

 

 

 

 

 

 

 

Skin

 

none or no change

 

scattered macular or papular eruption or erythema that is asymptomatic

 

scattered macular or papular eruption or erythema with pruritus or other
associated symptoms

 

generalised symptomatic macular, papular or vesicular eruption

 

exfoliative dermatitis or ulcerating dermatitis

Alopecia

 

 

 

 

 

 

 

 

 

 

Alopecia

 

no loss

 

mild hair loss

 

pronounced or total hair loss

 

—

 

—

Allergy

 

 

 

 

 

 

 

 

 

 

Allergy

 

none

 

transient rash,
drug fever < 38oC (<100.4oF)

 

urticaria,
drug fever 38oC (100.4oF),
mild bronchospasm

 

serum sickness, bronchospasm requiring parenteral medication

 

anaphylaxis

Local

 

 

 

 

 

 

 

 

 

 

Local

 

none

 

pain

 

pain and swelling with inflammation or phlebitis

 

ulceration

 

plastic surgery indicated

Fever of unknown origin

 

 

 

 

 

 

 

 

 

 

Fever of unknown origin

 

none

 

37.1 - 38.0o C
98.7o - 100.4o F

 

38.1 - 40.0o C
100.5 - 104o F

 

> 40.0oC (> 104o F) for less than 24hrs

 

> 40.0o C (> 104o F) for more than 24 hrs or accompanied by hypotension

Infection

 

 

 

 

 

 

 

 

 

 

Infection

 

none

 

mild

 

moderate

 

severe

 

life-threatening

 

59

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Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

Additional events

 

 

 

 

 

 

 

 

 

 

Asthenia

 

analogous to Karnofsky index (WHO grading)

 

 

 

 

 

 

 

 

Chills

 

analogous to fever

 

 

 

 

 

 

 

 

Peripheral oedema

 

analogous to weight gain

 

 

 

 

 

 

 

 

Anorexia

 

analogous to weight loss

 

 

 

 

 

 

 

 

 

--------------------------------------------------------------------------------

(1)The procedures for the Follow-up visit (Visit 10) for Study BA058-05-003 will
serve as the procedures performed at Day 1 (for Study BA058-05-005).  The
consent form will need to be signed if it was not signed during the
End-of-Treatment Visit (Visit 9) of Study BA058-05-003.

(2) Vital signs (blood pressure, pulse rate, body temperature, and respiration
rate) are to be recorded at each study visit.  Only the blood pressure
assessment on Day 1 (Visit 10) needs to be orthostatic.  Height is to be
measured at each visit in the standing position using a medical stadiometer. 
Weight is to be measured at each visit.  Orthostatic blood pressure is to be
measured initially after 5 minutes in the supine position and then again after
standing for three minutes.

(3) All routine urinalysis will be performed on a sample freshly voided during
the clinic visit.

(4) These blood samples are to be obtained under fasting conditions (N.P.O. for
8 hours; water is acceptable) in the morning of each scheduled study visit.

(5) Includes blood samples for PINP, bone-specific alkaline phosphatase, serum
osteocalcin and CTX.

(6) Twenty-four hour urine collection will be used for urinary calcium and
urinary creatinine measurements. Subjects will discard the 1st void and begin a
24-hour urine collection the day prior to the clinic visit.

(7) A 24-hour urine collection will be collected at Month 3 only if a sample was
not collected for the Day 1 (Visit 10).

(8) Each DXA for a given subject should be performed on the same machine, and if
available, preferably by the same technician

(9) Each DXA for a given subject should be performed on the same machine, and if
available, preferably by the same technician.  Only subjects who had wrist DXA
assessments in Study BA058-05-003 will have wrist DXAs performed.

(10) The subjects will maintain a diary throughout the study to record missed
doses of medication (including supplements) on a weekly basis; the diaries are
to be reviewed with the subject at each study visit.

 

60

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