Exhibit 10.11

 

Work Statement NB-1

 

WORK STATEMENT

 

This Work Statement NB-1 is entered into 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-1
and not defined in this Work Statement NB-1 are used with the meanings ascribed
to them in the Agreement.  This Work Statement NB-1 is attached to and becomes,
upon execution by both parties below but subject to the consummation by Radius
of an equity financing pursuant to which it shall have issued and sold shares of
its Series A-1 Convertible Preferred Stock, par value $0.01 per share, to
existing and/or new investors resulting in aggregate gross proceeds being
received by Radius in an amount equal to approximately sixty million U.S.
Dollars (US$60,000,000) (unless waived by Radius), 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-1 entitled “A Randomized, Double-blind, Placebo-controlled,
Comparative Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of
BA058 for Injection for Prevention of Fracture in Ambulatory Postmenopausal
Women with Severe Osteoporosis and at Risk of Fracture”.

 

This Work Statement NB-1 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

 

IN WITNESS WHEREOF the parties have executed this Work Statement NB-1 intending
it to take effect as an instrument under seal as part of the Agreement as of
March 29, 2011.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

 

 

 

 

 

 

 

 

By:

/s/ C. Richard Lyttle

 

By:

/s/ Claus Christiansen

Name:

C. Richard Lyttle

 

Name:

 

Title:

CEO and President

 

Title:

CEO

Date:

 

 

Date:

 

 

 

Acknowledged and Agreed:

 

 

 

 

 

 

 

xxxxxxx, Project Leader

 

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

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

 

Work Statement NB-1

Attachment A

 

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

 

Study Assumptions

 

Radius Health, Inc.

 

Protocol:  BA058-05-003, “A Randomized, Double-blind, Placebo-controlled,
Comparative Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of
BA058 for Injection for Prevention of Fracture in Ambulatory Postmenopausal
Women with Severe Osteoporosis and at Risk of Fracture”

 

Protocol Number

 

BA058-05-003

Number of Sites:

 

11

Denmark

 

3

Estonia

 

1

Lithuania

 

1

Romania

 

1

Poland

 

1

Czech Republic

 

2

Brazil

 

1

Hong Kong

 

1

Number of Patients to be Screened

 

20,000

Number of Patients to Enroll:

 

2,400

Enrollment Period:

 

6 months from last approval of the Protocol by applicable Regulatory Authorities

Treatment Period:

 

18 months

Safety Follow up Period

 

1 month

Visits per Completed Subject:

 

10

 

Clinical Trial Timeline

 

BA058-05-003 Milestones

 

Duration in Months

 

Estimated
Timeline

Regulatory Submissions

 

All Complete

 

1 Jan 2011

First Regulatory Approval

 

 

 

15 Feb 2011

Last Regulatory Approval

 

8 months (Brazil)

 

1 July 2011

IMP ready at site

 

 

 

30 March 2011

First Patient Randomized

 

 

 

31 March 2011

Enrollment Complete

 

6 months (after last Regulatory Approval)

 

1 March 2012

Treatment Period

 

18 months

 

1 Sep 2013

Last Patient Last Study Visit

 

1 month

 

1 October 2013

Database Lock

 

1.5 months

 

15 November 2013

Locked Database Transfer to Sponsor

 

 

 

16 November 2013

Site Close-out Visits

 

1.5 months

 

31 Dec 2013

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment A-1

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

 

Work Statement NB-1

Attachment B

 

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

 

BA058-05-003 Draft Protocol Version 3.0 10 August 2010 Cost Proposal Version 2
September 2010

 

Sponsor:

 

Radius Health, Inc.

 

 

Protocol ID:

 

BA058-05-003

 

 

Development Phase:

 

III

 

 

Disease:

 

Osteoporosis

 

 

Total # of Randomized Subjects (CCBR):

 

2,400

 

Less 15% due to Drop Out= 2,040

PK/PD Study; *samples for BA058 on 600 subjects, samples for s-calcium on 2,400
subjects:

 

All

 

Adjusted for Drop Out

ECG pre-and 60 minutes post dose:

 

All

 

Adjusted for Drop Out

Bone Biopsy:

 

200

 

 

Expected Date of FPFV:

 

Q1 2011

 

 

Expected Length of Recruitment (months):

 

 

 

 

Treatment Duration (months):

 

18

 

 

Number of visits:

 

10

 

 

Number of CCBR Clinics:

 

11

 

Assumes only CCBR sites

Number of potential study subjects to be prescreened:

 

20,000

 

 

 

Total Budget

 

EURO

 

 

Pre-screening/Advertisement

 

[*]

 

Only spine DEXA

35 % screen failure

 

[*]

 

Assumes 35% Screen Failure rate after PIC has been signed

Clinic Activities (randomized and completed)

 

[*]

 

Adjusted for Drop Out

BA058 PK Study; sample collection and clinic stay

 

[*]

 

No BA058 analysis, adjusted for Drop-out

CRO Activities

 

[*]

 

50% source data verification and adjusted for Drop Out

Central Lab Fee

 

[*]

 

Adjusted for Drop Out Includes sample shipment. Bone markers on 600 subjects
Local hematology (=less shipment cost)

Bone Biopsy (200 biopsies)

 

[*]

 

200 biopsies

CT-scan (payment to X-ray departments) (300 subjects)

 

[*]

 

300 Subjects end of study

Calcium and Vitamin D supplement

 

[*]

 

 

Sub Total budget (EURO)

 

[*]

 

 

Discount

 

[*]

 

 

Sub Total budget (EURO)

 

35,553,732

 

 

Sub Total budget (USD)

 

46,219,852

 

Assumes 1 EURO = 1.30 USD

Central Imaging Reading (USD)

 

[*]

 

All hip and spine DEXA central reading Local reading for eligibility. Wrist DEXA
central read on 900 subjects (300 per arm)

Central Imaging Pass Through (USD)

 

[*]

 

 

Total Budget (USD)

 

48,825,737

 

 

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment B-1

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

 

The pricing specified in this Budget is calculated based upon 2,400 subjects
randomized and entered into the clinical study and assumes a 35% screen-failure
rate after the Patient Informed Consent has been signed and a 15% drop-out rate,
the Budget will be adjusted as the study proceeds to reflect the actual
screen-failure rate and the actual drop-out rate and all pricing will be
adjusted in a pro rata fashion to reflect the actual study activities completed
by the study subjects.

 

Pass through Cost

 

EURO

Submission Fee to ERC

 

Included

Containers for 24-h urine collection

 

Included

Local Hematology Test’s

 

Included

Advertisement

 

Included

Monitoring Travel Expenses & Accommodations / other travels

 

Included

Shipments of imaging and labs

 

Included

Translation

 

Included

Investigator Meeting

 

Included

Data Monitoring Committee

 

Not Included

Patient insurance

 

Not included

Annual reports to the FDA

 

Not included

External advisory Board

 

Not included

Statistical Data analysis and Clinical Study Report

 

Not included

Purchase of Forteo

 

Not included(1)

 

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

(1) It is understood and agreed that Radius shall as part of the “Purchase of
Forteo” obligations cause the supplier of the Forteo product (Pharmarama
International Limited) to enter into a purchase agreement with NB that includes
delivery by Pharmarama DDP to the Aptuit Ltd. facility in Oxford United Kingdom
(“UK”) for packaging,  [*].

 

Payment Schedule

 

(a)  A portion of the purchase price for the Services shall be paid in cash and
the balance shall be paid by issuance to NB of shares of Radius Series A-6
Convertible Preferred Stock, $0.01 par value, at a price of $0.01 per share. 
The cash payment portion of the purchase price shall be subject to this Work
Statement NB-1 and the Agreement; the stock issuance portion of the purchase
price shall be made pursuant to a Stock Issuance Agreement (the “Stock Issuance
Agreement”).

 

(2)  The cash payment portion of the purchase price is comprised of a portion
denominated in EURO and a portion denominated in U.S. Dollars as noted in the
cost proposal set forth above.  The EURO portion is €35,553,732  and the U.S.
Dollar portion is $2,605,885.  This pricing is based upon 2,400 study subjects
randomized and a 35% screen-failure rate after the Patient Informed Consent has
been signed and a 15% drop-out rate and a pro rata adjustment to pricing based
upon the actual number of study subjects that are not the subject of
screen-failure and the actual clinical study activities that are completed prior
to drop-out for study subjects that drop-out.  Radius shall pay the EURO
denominated portion of the purchase price and the U.S. Dollar portion of the
purchase price separately in the applicable currency as set forth in Paragraphs
(3)-(9).

 

(3)  Radius has entered into a Letter of Intent dated September 3, 2010 with NB
pursuant to which Radius has funded an aggregate $1,500,000.00 of Radius’
aggregate cash payment obligations to NB in respect of the clinical study that
is the subject of Work Statement NB-1.  On the Effective Date, Radius will pay
NB a non-refundable cash fee of €5,649,144.20, representing 15.889% of Radius’
aggregate cash payment obligation to NB for the EURO denominated portion of the
clinical study, which amount shall be reduced by the aggregate $2,250,000.00
payment previously provided by Radius under the Letter of Intent and the two
extensions to such Letter of Intent described below, using the exchange rate for
buying EUROs with U.S. Dollars set forth in the Wall Street Journal (Online
Edition) Market Data Center at
http://online.wsj.com/mdc/public/page/marketsdata.html on the date(s) each
portion of such aggregate $2,250,000.00 payment

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment B-2

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

 

was made.  The initial $500,000 portion was paid September 8, 2010 and the
credit for such payment will use the exchange rate for that date (0.7865) to
convert U.S. Dollars to EUROS; the second $500,000 portion was paid October 19,
2010 and the credit for such payment will use the exchange rate for that date
(0.7283) to convert U.S. Dollars to EUROS.  Radius and NB entered into an
extension of the Letter of Intent on December 15, 2010 pursuant to which Radius
paid an additional $500,000 on December 19, 2010 and the credit for such payment
will use the exchange rate for December 17 (0.7584) to convert U.S. Dollars to
EUROS.  Radius and NB entered into a second extension of the Letter of Intent on
January 31, 2011 pursuant to which Radius paid an additional $750,000 on
February 3, 2011 and the credit for such payment will use the exchange rate for
February 3 (0.7334) to convert U.S. Dollars to EUROS.

 

In addition, on the Effective Date, Radius shall also pay NB or its designee a
non-refundable cash fee of $260,589 representing 10% of Radius’ aggregate cash
obligation to NB for the U.S. Dollar denominated portion of the clinical study
that is the subject of Work Statement NB-1.

 

(4)  Thereafter, Radius will pay NB on a calendar monthly basis commencing with
the month in which the first subject is enrolled in the clinical study and
ending the month that an aggregate 2,400 subjects have been enrolled in the
clinical study (“First Monthly Amount”) at the rate of €[*] per randomized
subject enrolled in the clinical study that is the subject of Work Statement
NB-1 for the EURO denominated portion of the clinical study and at the rate of
$[*] per randomized subject enrolled in the clinical study that is the subject
of Work Statement NB-1 for the U.S. Dollar denominated portion of the clinical
study.  These amounts represent 33.752% of Radius’ aggregate cash payment
obligation to NB in respect of the EURO denominated portion of the clinical
study that is the subject of Work Statement NB-1 and 7% of the U.S. Dollar
denominated portion of the clinical study that is the subject of Work Statement
NB-1.

 

(5)  Radius will thereafter pay NB €[*] per month for the first [*] ([*]) months
after patient randomization is completed (“Second Monthly Amount”) and €[*] per
month for the next [*] ([*]) months after patient randomization is completed
(“Third Monthly Amount”) for the EURO denominated portion of the clinical study
that is the subject of Work Statement NB-1. Radius shall also thereafter pay NB
or its designee in respect of the U.S. Dollar denominated portion of the
clinical study that is the subject of Work Statement NB-1 a Second Monthly
Amount equal to $[*] per month and a Third Monthly Amount equal to $[*] per
month during the periods when the Second Monthly Amount and the Third Monthly
Amount, as applicable, is payable.

 

Payment of each installment of the Second Monthly Amount and the Third Monthly
Amount shall be calculated based upon the estimated time that will be required
to complete the clinical study (following enrollment of the first study subject)
and lock the study database and transfer the study database to Radius.  The
parties, acting through the Project Committee will evaluate the study timeline
and adjust the Second Monthly Amounts and the Third Monthly Amounts to account
for delays or accelerations in the performance of the clinical study.

 

(6)   Each Second Monthly Amount and Third Monthly Amount payment due NB shall
be determined by subtracting payments (if any) previously made pursuant to the
Second Monthly Amount and the Third Monthly Amount from €[*] (in the case of the
EURO denominated portion of the clinical study) or from $[*] (in the case of the
U.S. Dollar denominated portion of the clinical study) and then dividing that
number by the number of months the Project Committee then determines it will
take to complete the clinical study that is the subject of this Work Statement
NB-1 and lock the study database and transfer the study database to Radius.

 

(7)  On a monthly basis, beginning with the month in which the last subject is
enrolled in the clinical study that is the subject of this Work Statement NB-1,
Radius shall request an update from the Project Committee with respect to the
projected timeline of the clinical study that is the subject to Work Statement
NB-1 and based upon the update provided by the Project Committee, Radius shall
calculate the payment due NB using the formula set forth in Paragraph (6) and
make payment to NB in accordance with Section 4.3 of the Agreement.

 

(8)  The Second Monthly Amount and the Third Monthly Amount represent,
respectively, 16.876% of Radius’ aggregate cash payment obligation to NB in
respect of the EURO denominated portion of the  clinical study that is the
subject of Work Statement NB-1 and, respectively, 16% and 40% of the U.S. Dollar
denominated portion of the  clinical study that is the subject of Work Statement
NB-1.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment B-3

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

 

(9)  The balance of Radius’ aggregate cash payment obligation to NB in respect
of the Euro denominated portion of the clinical study that is the subject of
Work Statement NB-1, (€[*] based on 2,400 patients randomized and a 35%
screen-failure rate after the Patient Informed Consent has been signed and a 15%
drop-out rate and a pro rata adjustment to pricing based upon the actual number
of study subjects that are not the subject of screen-failure and  the actual
clinical study activities that are completed prior to drop-out for study
subjects that drop-out) shall be paid in two equal installments of €[*]. The
balance of Radius’ aggregate cash payment obligation to NB in respect of the
U.S. Dollar denominated portion of the clinical study that is the subject of
Work Statement NB-1, ($[*] based on 2,400 patients randomized and a 35%
screen-failure rate after the Patient Informed Consent has been signed and a 15%
drop-out rate and a pro rata adjustment to pricing based upon the actual number
of study subjects that are not the subject of screen-failure and the actual
clinical study activities that are completed prior to drop-out for study
subjects that drop-out) shall be paid in two equal installments of $[*].  The 
first installment of each payment will be due and payable to NB when the study
database for the clinical study that is the subject of Work Statement NB-1 is
locked and transferred to Radius; the second installment is due and payable upon
the earlier of:  (i) acceptance of the Final Tables Listings and Figures for the
clinical study that is the subject of Work Statement NB-1; or (ii) eight weeks
after the database has been locked and delivered to Radius; provided that Radius
shall not be required to accept the Final Tables Listings and Figures if they do
not conform to the specifications set forth in the Protocol for Work Statement
NB-1 or embody data that is scientifically inconsistent and merit, in Radius’
reasonable opinion, a review of clinical study site records for such clinical
study purposes of confirming certain aspects of the underlying clinical study
data and results as reported to the clinical study database (each, a
“Nonconformity”).  If Radius identifies a Nonconformity prior to the expiration
of the 8-week period specified in Paragraph (f)(ii), Radius shall deliver notice
to NB of such Nonconformity specifying the steps that Radius believes are
necessary to resolve such Nonconformity and bring the Final Tables Listings and
Figures into conformity.  Upon receipt of such notice, NB shall take appropriate
steps to investigate and resolve the Nonconformity and the 8-week period shall
be extended day-for-day while NB investigates the Nonconformity and either
updates the clinical study database and redelivers it to Radius or provides
Radius with a report detailing the results of NB’s investigation of the
Nonconformity and indicating why the Nonconformity does not require that the
clinical study database be updated.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment B-4

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

 

Work Statement NB-1

Attachment C

Materials Provided by Either Party

 

Trial Activities & Delegation of Responsibilities

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

 

Sponsor & Service provider Governance

 

 

 

 

 

 

CCBR - Radius Governance Committee

 

ü

 

ü

 

Sponsor and Service provider will 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.

Health Authority, EC, IRB Queries & Response

 

ü

 

ü

 

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.

Informed Consent Form (ICF, PIS)

 

ü

 

R

 

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

 

Attachment 2, Attachment C-1

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

Ethics Committees/IRB Submissions & Updates

 

ü

 

 

 

Service Provider will be responsible for all country and site Ethics Committees
and/or local IRBs submissions.

FDA SAE Submission & Follow Up(s)

 

 

 

ü

 

Sponsor will be responsible for FDA SAE submissions. 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 FDA. 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

 

 

 

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

 

 

 

 

 

 

BD Pen II Manufacture

 

 

 

ü

 

Sponsor will be responsible to manufacture to BD Pen injection device

BA058 80 mcg Cartridge Manufacture

 

 

 

ü

 

Sponsor will be responsible to manufacture the BA058 80 mcg cartridges.

BA058 Placebo Manufacture

 

 

 

ü

 

Sponsor will be responsible to manufacture the BA058 placebo cartridges.

Qualified Person for Drug Release

 

 

 

ü

 

Sponsor will be responsible to provide a Qualified Person (QP) for drug release
in the EU, if necessary.

Study Drug Shipping

 

 

 

ü

 

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

Forteo procurement

 

ü

 

ü

 

Service provider will be responsible to procure the Forteo clinical trial
material from Pharmarama International Limited (“Pharmarama”) under terms that
include delivery by Pharmarama DDP to the Aptuit Ltd. facility in Oxford England
for packaging. Sponsor, however, shall be responsible for the logistics and
costs of such clinical trial material.

Package Clinical Trial Materials

 

 

 

ü

 

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

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment C-2

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

Vitamin D & Calcium

 

ü

 

 

 

Service provider will be responsible to procure the Vitamin D & Calcium required
to be taken concomitantly during the study.

Country specific labels

 

ü

 

ü

 

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

Instructions for Use - BA058 BD Pen & Forteo

 

R

 

ü

 

Sponsor will be responsible to create and provide an Instructions for Use for
the BA058 BD Pen and Forteo User’s Manual in English. Service provider will be
responsible for translating the Instructions for Use and Forteo User Manual, as
required by local regulations.

BD 31g 8mm Needles

 

 

 

ü

 

Sponsor will be responsible to procure and supply the BD 31g 8 mm needles for
use with the BA058 cartridges and Forteo pens.

Sharps containers

 

ü

 

 

 

Service provider will be responsible to provide each patient with a sharps
container for disposal of study needles.

Alcohol Swabs

 

ü

 

 

 

Service provider will be responsible to provide each patient with alcohol swabs.

Tote Bags/Coolers

 

ü

 

 

 

Service provider will be responsible to provide each patient with tote bags and
coolers.

Study Drug Release & Distribution (IVRS)

 

 

 

ü

 

Sponsor will be responsible to release study drug and distribute to clinical
study sites. The sponsor will be responsible to contract an IVRS vendor.

Study Drug Reconciliation — Patient, Site, & Study

 

ü

 

R

 

Service provider will be responsible to perform drug accountability during the
clinical study. Each study cartridge and Forteo pen 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. The patient and site drug reconciliation
documentation will be sent to the sponsor for review on a regular basis.

Study Drug Destruction

 

 

 

ü

 

Sponsor will be responsible for final study drug destruction.

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

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment C-3

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

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.

Clinical Trial Project Plan

 

ü

 

A

 

Service provider 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.

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.

Medical Monitoring

 

ü

 

R

 

Service provider will be responsible for medical monitoring. Sponsor will review
Service provider’s performance and may request adjustments.

Vendor Management - Labs, X-ray, Dexa, Renal, Imaging, ECG

 

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 - PK, Antibody, Drug Manufacture/Package, IVRS

 

 

 

ü

 

Sponsor will be responsible for the vendor management of the PK sampling,
Antibody testing, and Study drug manufacture, packaging, and/or procurement.

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 recruited,
cumulative number screened, number screened within the reporting week, number
screened but not enrolled, number failed screening, and number enrolled.

 

Attachment 2, Attachment C-4

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

Site Selection

 

ü

 

A

 

Service provider will be responsible for site identification and selection for
participation in the clinical study. Sponsor will be responsible for approving
the list of sites identified by the Service provider.

Site Management

 

ü

 

 

 

Service provider will be responsible for site management activities.

Site Confidentiality Agreements

 

ü

 

R

 

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

 

 

 

 

 

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..

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. Sponsor will be required to
approve the Service provider’s selection of monitors.

Monitor Travel Expense

 

ü

 

 

 

Service provider will be responsible for monitoring expenses.

CRA Meetings

 

ü

 

R

 

Service provider will be responsible for scheduling, conducting, and creating
meeting minutes for CRA meetings. The Service provider will include the Sponsor
as a participant to the CRA meetings.

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

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment C-5

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

an ad-hoc basis as required by the Sponsor or Service provider.

Sponsor Meeting Minutes

 

ü

 

A

 

Service provider will be responsible to create the meeting minutes for the
Sponsor meetings and circulate a draft within 24 hours. Sponsor 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. 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 investigator meeting training materials.

Central Imaging Analysis (Fracture, BMD, Renal)

 

ü

 

 

 

Service provider will be responsible to provide central imaging services to
assess the protocol required measures for fracture, bone mineral density, and
renal tissue mineralization and function.

Fracture Adjudication

 

ü

 

R

 

Service provider will be responsible to assess all radiographs by a blinded,
independent assessor (radiologist) on the basis of existing baseline and
study-acquired vertebral deformity, and fracture will be assessed according to
the severity scale of Genant (1993). Assessment will be done according to the
procedure set forth in the Protocol.

Protocol Deviation & Waiver

 

ü

 

A

 

Service provider will be responsible to identify and/or collect all protocol
deviations. For prospective deviations, the Sponsor Medical Monitor will need to
approve prior to the deviation occurring. For deviations identified
retrospectively, the Service provider will send all protocol deviations and
corrective and preventative actions to the Sponsor and will maintain a log of
the deviations and actions. In the event a site requests a protocol waiver, the
Service provider will communicate the request and data to the Sponsor for
approval.

Sponsor Project Update Reports

 

ü

 

 

 

Service provider will be responsible to create monthly study status update
reports.

Trial Master File

 

ü

 

 

 

Service provider will be responsible to

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment C-6

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

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.

Site Trial File

 

ü

 

 

 

Service provider will be responsible to insure 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

 

 

 

Service provider will be responsible for all site payments.

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 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

 

A

 

Service provider will be responsible for creating flags for abnormal lab values.
Sponsor will be responsible for the approval of the lab value flags.

Lab Specimen Management, Shipping & Reconciliation

 

ü

 

 

 

Service provider will be responsible for lab sample management, shipping,
storage, 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 until all lab
data are final and reported.

 

Attachment 2, Attachment C-7

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

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

 

 

 

ü

 

Sponsor will be responsible for PK sampling and data reporting.

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 & handling plan

 

ü

 

A

 

Service provider will be responsible to create the Data Management and Data
Handling Plan for the study upon approval of the CRF. Sponsor will be required
to approve the plans.

Annotated Case Report Form

 

ü

 

A

 

Service provider will be responsible to create the Annotated Case Report Forms
based on CDISC SDTM. Sponsor will be required to approve the annotated CRF.

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.

CRF Completion Instructions

 

ü

 

R

 

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

 

ü

 

 

 

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

Data Cleaning & Query Management

 

ü

 

 

 

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

Double Data Entry

 

ü

 

 

 

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

 

Attachment 2, Attachment C-8

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

for Sponsor review.

Data Transfers & Merge

 

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

 

A

 

Service provider will be responsible to prepare for a DSMB meeting to clean the
data and manage the queries and prepare a database transfer to the Sponsor’s
statistician. The database transfer specification will be provided to the
Sponsor for approval prior to the first data transfer.

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 (during screening), Baseline Demographics (during screening),
Adverse Events (monthly), Concomitant Medications (monthly), Study Drug
Administration (monthly), Patient Vertebral and Non Vertebral Fractures
(monthly), Patient BMD all sites (monthly), Abnormal Labs (monthly), Elevated
Calcium (monthly)

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. Sponsor will be responsible
to approve the events and medications are coded 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

 

ü

 

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

 

ü

 

A

 

The Service provider will be responsible to create the Local Tolerance Diary.
The Sponsor will be responsible for approving the Local Tolerance Diary prior to
the

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment C-9

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve
R = Review

 

Nordic
Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

document’s submissions.

Drug Compliance Diary

 

ü

 

A

 

The Service provider will be responsible to create the Drug Compliance Diary.
The Sponsor will be responsible for approving the Drug Compliance Diary prior to
the document’s submissions.

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.

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

 

 

 

 

 

 

Safety Monitor

 

ü

 

 

 

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

Safety Plan

 

ü

 

A

 

Service provider will be responsible to develop a safety 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

 

Attachment 2, Attachment C-10

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve

 

Nordic

 

 

 

 

R = Review

 

Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

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).

Serious Adverse Event Narrative

 

ü

 

ü

 

Sponsor and Service provider will be responsible to create the SAE narrative for
reporting in the CIOMS and providing to the Medical Writer for the clinical
study report.  Sponsor is responsible for reviewing and approving the SAE
narrative prior to approving the CIOMS for submission.

Annual & Periodic Safety Update Generation & Filing

 

ü

 

A

 

Service provider will be responsible to create annual safety reports to update
Health Authorities in the EU and Hong Kong.  Sponsor will be responsible to
approve the annual safety reports prior to submission. Sponsor is responsible
for creating and submitting annual reports to the FDA

Health Authority Reporting

 

ü

 

ü

 

Sponsor will be responsible to submit SAE CIOMS Initial and Follow up to the
FDA.  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 7 or 15 days depending on the type of SAE identified in the Safety 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.  Sponsor will submit final safety report to FDA
and NB

 

Attachment 2, Attachment C-11

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve

 

Nordic

 

 

 

 

R = Review

 

Biosciences

 

Radius

 

Expectation

 

 

 

 

 

 

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.

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.

QT Prolongation Analysis

 

 

 

ü

 

Sponsor’s statistician will be responsible to generate the programming and
analyses for the ECG data collected for determination of QT Prolongation

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 of the safety narratives for the CSR during the clinical study.  The
Sponsor’s Medical Writer will be responsible for 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.

 

Attachment 2, Attachment C-12

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

 

ü = Owner

 

Activity Responsible

 

 

A = Approve

 

Nordic

 

 

 

 

R = Review

 

Biosciences

 

Radius

 

Expectation

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).

 

Attachment 2, Attachment C-13

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

 

Work Statement NB-1

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 Writer/Coder

 

Lina Saem Stoy

 

[*]

 

Lead CRA

 

Anders Enok Olsen

 

[*]

 

Head of Central Laboratory

 

Per Qyist

 

[*]

 

Clinical Regulatory Coordination

 

Lisa Thomsen

 

[*]

 

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment D-1

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

 

Work Statement NB-1

Attachment E

Protocol or Protocol Summary

 

Attachment 2, Attachment E-1

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

 

CLINICAL STUDY PROTOCOL

 

[g17732la09i001.gif]

 

A Randomized, Double-blind, Placebo-controlled, Comparative Phase 3 Multicenter
Study to Evaluate the Safety and Efficacy of BA058 for Injection for Prevention
of Fracture in Ambulatory Postmenopausal Women with Severe Osteoporosis and at
Risk of Fracture

 

·      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 BA058-05-003

 

 

 

 

 

·  EudraCT Number:

 

·      2010-022576-30

 

 

 

 

 

·  Protocol Date (Version):

 

·      2 December 2010 (Version 1.0)

 

 

 

 

 

·  Study Sponsor:

 

·      Radius Health, Inc. (RADIUS)

201 Broadway, 6th Floor
Cambridge, MA 02139, USA
Tel:  617.551.4700  Fax:  617.551.4701

 

 

 

 

 

·  Sponsor Medical Monitor:

 

·      Louis St.L. O’Dea, MB BCh BAO. FRCP(C)

Chief Medical Officer, Radius Health, Inc.
Tel:  617.551.4706.  Fax:  617.551.4701.
Email:  lodea@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

 

 

 

 

 

·  Study Site:

 

·      Multicenter; international

 

 

 

 

 

·  Principal Investigator:

 

·      TBD

Address
Contacts

 

·              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.

 

Attachment 2, Attachment E-2

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

 

Radius Health, Inc.

Confidential

 

 

PROTOCOL SYNOPSIS

 

·              Title:      A Randomized, Double-blind, Placebo-controlled,
Comparative Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of
BA058 for Injection for Prevention of Fracture in Ambulatory Postmenopausal
Women with Severe Osteoporosis and at Risk of Fracture

·              Protocol Number:  BA058-05-003

·              Phase:  3

·              Test Drug:  BA058 for Injection 80 µg

·              Study Objectives:

 

The primary objective of this study is to determine the safety and efficacy of
BA058 for Injection 80 µg when compared to a matching Placebo for prevention of
vertebral fracture in otherwise healthy ambulatory postmenopausal women at risk
of fracture from severe osteoporosis.  Patients, investigators and independent
assessors will be blinded as to treatment for that outcome.  The secondary
outcomes, also double-blind, of this study are to determine the safety and
efficacy of BA058 80 µg when compared to Placebo for prevention of non-vertebral
fractures and for change in vertical height.  Additional key secondary efficacy
outcomes include bone mineral density of spine, hip and femoral neck and
hypercalcemia when compared to teriparatide (Forteo®/Forsteo®, Eli Lilly and
Co.), which will be assessor-blind.

 

The specific objectives of this study are to:

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on lumbar spine, hip, and femoral neck bone mineral density
(BMD) in otherwise healthy ambulatory postmenopausal women with severe
osteoporosis when compared to teriparatide.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of non-vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the overall safety and tolerability of 18 months of
treatment with BA058 80 µg, and specifically the number of patients with
hypercalcemic events, in otherwise healthy ambulatory postmenopausal women with
severe osteoporosis when compared to teriparatide and Placebo.

 

·                  Provide additional evidence of bone safety through
histomorphometric assessment of bone biopsy samples in a randomized subset of
patients from the BA058 80 µg and Placebo groups.

 

·                  Provide additional evidence of renal safety through
radiological assessment by CT scan of a randomized subset of patients from the
BA058 80 µg, Placebo and teriparatide groups.

 

·              Study Population:

 

Inclusion Criteria:

 

Otherwise healthy ambulatory postmenopausal (> 5 years) women from 50 to 85
years of age (inclusive) who meet the study entry criteria and have provided
written informed consent are eligible for the study.  The women are to have a
BMD T-score < -2.5 and > -5.0 at the lumbar spine or hip (femoral neck) by dual
energy x-ray absorptiometry (DXA) and radiological evidence of 2 or more mild or
one or more moderate lumbar or thoracic vertebral fractures, or history of low
trauma forearm, humerus, sacral, pelvic, hip, femoral, or tibial fracture within
the past 5 years.  Postmenopausal women older than 65 who meet the above
fracture criteria but have a T-score < -2.0 and > -5.0 may be enrolled.  Women
older than 65 who do not meet the fracture criteria may also be enrolled if
their T-score is <-3.0 and > -5.0.

 

All patients are to be in good general health as determined by medical history,
physical examination (including vital signs) and clinical laboratory testing. 
Serum calcium, PTH(1-84), serum phosphorus and serum alkaline

 

Attachment 2, Attachment E-3

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

 

phosphatase values must be within the normal range during the Screening Period. 
Serum 25-hydroxy Vitamin D must be above 15 ng/mL and within 3 times the upper
normal range to be eligible for enrollment.  The resting 12-lead ECG obtained
during screening should have no clinically significant abnormality and a QTc
(Bazett’s correction) of < 470 msec.  Patients with more than four mild or
moderate fractures, or any severe fractures, will be excluded from the study. 
In addition, patients with fewer than 2 evaluable lumbar vertebrae or patients
with unevaluable hip BMD will be excluded from the study.

 

Patients with unexplained elevation of serum alkaline phosphatase, with a
history of Paget’s disease, of any cancer within the past 5 years other than
basal cell or squamous cancer of the skin, will be ineligible for enrollment. 
Also, patients with a history of Cushing’s disease, hyperthyroidism, hypo- or
hyperparathyroidism or malabsorptive syndromes within the past year are also
ineligible for enrollment.  Patients who have ever received treatment with a PTH
or PTHrP drug will be excluded.  Treatment with bisphosphonates, fluoride or
strontium in the past 5 years, or treatment with androgens, other anabolic
steroids, corticosteroids or selective estrogen receptor modulators within the
past 12 months will also exclude patients from enrollment. Patients who had a
short course of bisphosphonate treatment (3 months or less) and were intolerant
of the treatment may be considered for study participation.  Estrogens
administered as hormone replacement therapy (HRT), with or without progestins,
are not exclusionary. Patients who have participated in a clinical study of any
novel unapproved medication in the past 12 months will also be excluded from
participation.

 

The specific inclusion and exclusion criteria are described in Sections 4.2 and
4.3 of the protocol, respectively.

 

·              Study Design and Methodology:

 

Number of Patients

 

A total of 2400 patients are planned to be enrolled in the study in 11 medical
centers.

 

Design

 

This is a randomized, double-blind, placebo-controlled, comparative Phase 3,
multicenter international study to evaluate the efficacy and safety of
BA058 80 µg in the prevention of fracture in otherwise healthy ambulatory
postmenopausal women with severe osteoporosis.

 

A total of 2400 eligible patients will be randomized equally to receive one of
the following: BA058 80 µg, a matching Placebo, or teriparatide 20 µg for 18
months.  Study drug will be blinded to patients and medical personnel until the
randomization process is completed.  Treatment with BA058 80 µg or Placebo will
remain blinded to all parties throughout the study.  As a proprietary prefilled
drug and device combination marketed product, teriparatide cannot be repackaged
and blinded.  Study medication will be self-administered daily by SC injection
for a maximum of 18 months.  Patients unable to self-administer drug may be
injected by a third party after appropriate training of that person by the study
site personnel.

 

The dosages of study medications and the number of patients to be enrolled are
shown below:

 

Treatment
Regimen

 

Study Medication

 

Daily
Dose (SC)

 

Duration

 

Number of
Patients

 

1

 

BA058

 

80 µg

 

18 months

 

800

 

2

 

Placebo

 

—

 

18 months

 

800

 

3

 

Teriparatide

 

20 µg

 

18 months

 

800

 

 

 

 

 

 

 

Total

 

2400

 

 

All enrolled patients will also receive Calcium and Vitamin D supplementation
from the time of enrollment until the end of the Treatment Period; it will be
recommended to patients that they also continue these supplements through the
Follow-up Period.

 

Attachment 2, Attachment E-4

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

 

Study Visits

 

Upon signing of the informed consent, patients will enter a 1-4 week period of
screening and prestudy training.  Patients will be trained on
self-administration of study drug and on recording of medication usage and local
tolerance.  After eligibility is assessed during the Screening period, a one
week Pretreatment period is used to collect baseline data.  Once enrolled,
patients will return to their study center for safety and efficacy assessments
at baseline (Day 1) and 1, 3, 6, 9, 12, and 18 months, and at any other time as
warranted by safety, efficacy or compliance concerns.  A final study visit is
planned one month after the last dose of study drug.

The study periods and number of clinic visits are summarized below:

 

Study
Period

 

Duration of
Study Period

 

Scheduled
Visits (#)

 

1.

Screening

 

1-3 weeks

 

1

 

2.

Pretreatment

 

1 week

 

1

 

3.

Treatment

 

78 weeks

 

7

 

4.

Follow-up

 

4 weeks

 

1

 

 

Total

 

84-86 weeks

 

10

 

 

Procedures and Assessments

 

Efficacy

 

The primary efficacy endpoint will be the number of BA058-treated patients
showing new vertebral fractures at End-of-Treatment when compared to Placebo. 
New incident vertebral fractures will be evaluated according to the method of
Genant (1).  Efficacy assessments will therefore include documentation of the
incidence of clinical and radiographic fractures of the lumbar and thoracic
spine.  Patients will undergo baseline and End-of-Treatment antero-posterior and
lateral radiographs of the lumbar and thoracic spine.  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 fracture
will be assessed according to a set of pre-determined criteria.  A second
blinded radiologist will review the assessment of the first reviewer for all
patient 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.  A standardized graded scale of severity of
the vertebral deformity will be evaluated according to the method of Genant (1).

 

Secondary efficacy parameters will also include reduction in the incidence of
non-vertebral fractures (wrist, hip, rib, etc.) and reduction in moderate and
severe vertebral fractures.  Clinical fracture occurring de novo at these
anatomical sites during the study will also be assessed and analyzed.  Other
secondary efficacy endpoints will include changes in BMD of spine, hip, and
femoral neck, and wrist from baseline to end-of-treatment as assessed by DXA. 
Patients will undergo BMD assessments at Screening (spine and hip; all
patients), at Day 1 (wrist; in a subset of patients), and at Months 6, 12 and 18
(End-of-Treatment) of study participation.  Any patient who shows a continuing
significant deterioration (>7%) of BMD at spine or hip will have the assessment
repeated and, if confirmed, will be discontinued from the study.  Patients
sustaining an incident vertebral or non-vertebral fragility fracture will be
informed of the finding and offered the opportunity to remain in or discontinue
from the study.

 

Additional secondary endpoints will include change in standing height and
changes in serum bone markers across treatment, such as PINP, osteocalcin, and
bone-specific alkaline phosphatase.  Serum C-telopeptides (CTX), a marker of
bone resorption and collagen breakdown, will be measured and reported.  Bone
markers will be assessed Pretreatment and at Months 6, 12 and 18
(End-of-Treatment).  Urine samples will be collected for the measurement of
calcium and creatinine to determine the Calcium:Creatinine ratio.  The
Calcium:Creatinine ratio will be measured at each visit during the Treatment
Period.  The frequency of hypercalcemia across treatment groups will also be
assessed.

 

Attachment 2, Attachment E-5

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

 

Patients who discontinue study participation prematurely will undergo
End-of-Treatment and End-of-Study assessments once their discontinuation is
confirmed.

 

Safety

 

Safety evaluations to be performed will include physical examinations, vital
signs, 12-lead ECGs, clinical laboratory tests, and monitoring and recording of
adverse events.  Specific safety assessments will include post-dose (4 hours)
determination of serum calcium, determination of Creatinine Clearance, post-dose
ECG assessments at selected visits, and assessments of postural hypotension (60
minutes post-dose) at selected clinic visits.

 

The incidence and severity of adverse events by dose and cumulative dose and
pathological changes in hematology, chemistry and urinalysis data will be
recorded and summarized.  Changes in physical examination (including height),
vital signs, ECG and clinical laboratory tests will be descriptively
summarized.  Shift frequencies will be summarized for clinical laboratory tests.

 

Injection sites will be graded to assess local tolerance to study medication.

 

ECG and safety laboratory assessments will be performed at all scheduled visits
and at any unscheduled visit as deemed necessary by the Investigator.  QT
interval assessments will be performed for all study subjects across the
Treatment Period.

 

Bone biopsy of the iliac crest will be performed in a subset of patients
receiving BA058 80 µg and Placebo (up to 100 per group to obtain 75 evaluable
biopsies per treatment group) between Visits 8 and 9 for assessment of
quantitative bone histomorphometry using a duel-labeling procedure.  All bone
biopsies will be read blinded to treatment at a central specialized facility.

 

A further subset of patients, 100 per treatment group in all 3 groups, will
undergo a renal CT scan at the end of the study, which will also be read
(blinded as to treatment) centrally, to assess the renal parenchyma and
collecting system.

 

Study safety will be monitored by an independent Data Safety Monitoring Board.

 

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).

 

Statistical Considerations:

 

Sample Size

 

A sample size of 622 patients per treatment arm provides 90% power at a
two-sided alpha of 0.05 to detect a superiority difference of 4% between placebo
patients and BA058 80 µg for injection-treated patients on vertebral fracture
incidence.  To ensure an evaluable population of 622 patients, an overall sample
size of 800 patients per treatment arm will be recruited.  For statistically
powered secondary endpoints the sample size will have greater than 90% power at
an alpha of 0.05 to detect a 1.15%, 2.45%, and 2.00% difference for spine, hip,
and femoral neck BMD, respectively, between BA058 and teriparatide.  The study
sample size will also provide more than 90% power to detect differences between
BA058 and teriparatide in the number of patients reporting one or more events of
hypercalcemia.

 

Baseline Comparisons

 

Baseline characteristics, medical history, physical examination, vital signs and
ECG, will be summarized using standard descriptive statistics by treatment
group. Specific demographic and baseline parameters will be tested for overall
agreement across treatment groups using one-way ANOVA or Chi-square tests as
appropriate for the type of data.

 

Efficacy Analyses

 

The primary efficacy endpoint will be the number of BA058-treated patients
showing new vertebral fractures at End-of-Treatment when compared to Placebo.

 

Attachment 2, Attachment E-6

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

 

Key secondary endpoints that will be statistically analyzed include change in
BMD (spine, hip, and femoral neck) and differences in the number of patients
reporting one or more events of hypercalcemia from baseline to End-of-Treatment
for BA058 80 µg when compared to teriparatide.  Additional secondary efficacy
endpoints will include the change in vertical height in BA058 80 µg patients
when compared to Placebo and the incidence of BA058 80 µg patients with new
non-vertebral fractures from baseline to End-of-Treatment when compared to
Placebo.  Severity of vertebral fractures, fracture incidence over time by
treatment group, and new vertebral fractures in teriparatide patients compared
to Placebo will also be assessed.

 

Other efficacy endpoints will include change in wrist BMD in BA058-treated
patients, and changes in serum PINP, bone-specific alkaline phosphatase,
osteocalcin, and CTX across treatment.

 

Population PK/PD Analysis

 

Samples for measurement of serum levels of BA058 will be taken to evaluate
population PK effects on demographics, efficacy, and safety.

 

Safety Analysis

 

All patients who receive at least one dose of study medication will be included
in the safety analysis that will be performed on the following parameters:

 

Incidence and severity of AEs; dose and cumulative dose at which the AE
occurred.

 

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

 

Frequency of hypercalcemia will also be compared across treatment groups.

 

Bone histomorphometry as assessed by bone biopsy at End-of-Treatment in a
randomized subset of BA058 and Placebo patients.

 

Renal safety as assessed at End-of-Treatment by renal CT scan in a randomized
subset of patients in all treatment groups.

 

All AEs collected prior to first injection will be separately summarized in a
fashion similar to the TEAEs.

 

Treatments Administered:

 

BA058 80 µg Drug Product for Injection (2.0 mg/mL BA058 in 5 mg/mL tri-hydrate
sodium acetate and 5mg/mL of phenol (preservative) adjusted at pH 5.1 with
acetic acid) will be supplied as a liquid in a 1.5 mL Type 1 glass cartridge and
is stored refrigerated at 5 ± 3ºC.  The multi-dose cartridge is designed to
deliver a dose of 80 µg of BA058 in 40 µL of fluid or a half dose of 40 µg of
BA058 in 20 µL of fluid when inserted into the Pen Injector device.  Each
cartridge contains enough study medication to deliver the required daily dose
for 30 days.  Patients will be provided with a sufficient number of cartridges
to continue on treatment until the next scheduled clinic visit.  Study
medication should be stored in refrigerated conditions (2-8 ºC) until dispensed
for use.  In-use storage may be at room temperature, up to 25 ºC for 30 days.

 

Placebo is formulated similarly but without active BA058 and will be similarly
supplied as a liquid in a 1.5 mL Type 1 glass cartridge and is stored
refrigerated at 5 ± 3ºC.  The multi-dose cartridge is designed to deliver a dose
of Placebo in 40 µL of fluid when inserted into the Pen Injector device.  Each
cartridge contains enough study medication to deliver the required daily dose
for 30 days.  Storage and dispensing conditions will match those of active study
drug.

 

Teriparatide (rDNA origin) injection (250 µg/mL) will be supplied in multi-dose
disposable pens containing a glass cartridge.  Each pen contains enough study
medication to deliver the required daily dose for 28 days.  Study medication
should be stored in refrigerated conditions (2-8 ºC) until dispensed for use. 
In use storage should also be in refrigerated conditions, 2-8 ºC.

 

Calcium (500—1000 mg) and Vitamin D (400—800 IU) supplements will be provided at
the study site.

 

Attachment 2, Attachment E-7

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

 

Duration of Subject Participation:

 

The maximum total duration of study participation for an individual patient is
approximately 20 months from the initial screening visit to the completion of
final study evaluations.  Patients will complete screening and study-specific
procedures within 4 weeks.  After completion of the Screening and Pretreatment
Periods, patients will be randomized and will receive the first dose of study
medication on Day 1 of the Treatment Period.  The Treatment Period will be a
maximum of 18 months with daily SC dosing.  After completion of dosing, patients
will enter the Follow-up Period for 1 month.  The End-of-Study Visit will be
scheduled at the end of the Follow-up Period and patients will be terminated
from the study.

 

Post-study Treatments and Assessments:

 

Placebo Patients

 

Placebo patients who complete 18 months of study participation or experience a
clinical fracture will be given the opportunity to receive treatment with a
bisphosphonate for 24 months.  Patients will receive standard-of-care management
including assessment of BMD during this period.

 

BA058 Patients

 

BA058 patients who complete 18-months of study participation will be given the
opportunity to receive an additional 6 months of treatment with BA058 80 µg, to
assess the safety and efficacy of BA058 80 µg over,a total of 24 months of
treatment.  On completion of BA058 treatment, patients will be assessed for
maintenance of BMD benefit over 12 months post-treatment or will receive a
bisphosphonate to assess the benefit of sequential treatment with bisphosphonate
after BA058, for 12 months.

 

Teriparatide Patients

 

There will be no post-study treatments or assessments for patients completing
treatment with teriparatide.

 

Attachment 2, Attachment E-8

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

 

 

TABLE OF CONTENTS

 

Table of Contents

9

List of Abbreviations

12

1.0

INTRODUCTION

14

 

1.1

Background Information

14

 

1.2

Drug under Study

15

 

1.3

Study Rationale and Selection of Doses

18

 

 

1.3.1

Study Rationale

18

 

 

1.3.2

Study Design and Rationale for Placebo

18

 

 

1.3.3

Study Population

19

 

 

1.3.4

Selection of Endpoints

20

 

 

1.3.5

Selection of Dose

20

2.0

STUDY OBJECTIVES

22

3.0

INVESTIGATIONAL PLAN

23

 

3.1

Overall Design and Study Plan

23

 

 

3.1.1

Screening Period

25

 

 

3.1.2

Pretreatment Period

26

 

 

3.1.3

Treatment Period

26

 

 

3.1.4

Follow-up Period

27

4.0

SELECTION OF STUDY POPULATION

28

 

4.1

Number of Subjects

28

 

4.2

Inclusion Criteria

28

 

4.3

Exclusion Criteria

29

 

4.4

Withdrawal of Patients from the Study

31

 

4.5

Temporary Suspension of Treatment

32

 

 

4.5.1

Treatment Suspension due to Hypercalcemia

33

 

 

4.5.2

Treatment Suspension due to Hypercalciuria

34

 

4.6

Replacement of Patients

35

5.0

STUDY TREATMENTS

36

 

5.1

Study Medications

36

 

 

5.1.1

BA058 80 µg, Placebo and Teriparatide

36

 

 

5.1.2

Calcium and Vitamin D Supplements

36

 

5.2

Packaging, Labeling and Storage

37

 

 

5.2.1

Packaging

37

 

 

5.2.2

Labeling

37

 

 

5.2.3

Storage

37

 

5.3

Treatment Assignment

37

 

5.4

Study Medication Administration

38

 

5.5

Treatment Compliance

39

 

5.6

Unblinding of Study Medication

39

 

 

5.6.1

Medical Emergency

39

6.0

CONCOMITANT MEDICATIONS

40

 

6.1

Concomitant Medications

40

 

6.2

Prohibited Medications

41

7.0

STUDY ASSESSMENTS

42

 

Attachment 2, Attachment E-9

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

 

 

7.1

Clinical Procedures/Assessments

42

 

 

7.1.1

Informed Consent

42

 

 

7.1.2

Medical History

42

 

 

7.1.3

Physical Examination

43

 

 

7.1.4

Vital Signs, Weight and Height

43

 

 

7.1.5

Electrocardiogram

43

 

 

7.1.6

Clinical Laboratory Evaluations

43

 

 

7.1.7

Serum Markers of Bone Metabolism

46

 

 

7.1.8

Clinical and Radiologic Evaluation of Fractures

46

 

 

7.1.9

Bone Mineral Density

47

 

 

7.1.10

Quantitative Bone Histomorphometry Assessment

48

 

 

7.1.11

Renal assessment by CT Scan

48

 

 

7.1.12

BA058 Serum Level and Antibody Assessments

48

 

 

7.1.13

Local Tolerance

48

 

 

7.1.14

Patient Diaries

49

 

 

7.1.15

Activity and Diet

50

8.0

ADVERSE EVENTS AND SAFETY EVALUATION

50

 

8.1

Definitions, Documentation, and Reporting

50

 

 

8.1.1

Adverse Event Definition

50

 

 

8.1.2

Serious Adverse Event Definition

50

 

8.2

Monitoring of Adverse Events and Period of Observation

51

 

8.3

Procedures for Recording and Reporting AEs and SAEs

52

 

8.4

Rules for Suspension of the Study

54

9.0

Statistical Procedures

55

 

9.1

Sample Size

55

 

9.2

Randomization, Stratification and Blinding

56

 

9.3

Populations for Analysis

57

 

 

9.3.1

Safety Population

57

 

 

9.3.2

Modified Intent-to-Treat Population

57

 

 

9.3.3

Per Protocol Population

57

 

9.4

Procedures for Handling Missing, Unused, and Spurious Data

57

 

9.5

Statistical Methods

57

 

 

9.5.1

Baseline Comparisons

57

 

 

9.5.2

Efficacy Analysis

57

 

 

9.5.3

Safety Analysis

60

 

 

9.5.4

Interim Analysis

60

 

 

9.5.5

Procedures for Reporting Deviations to Original Statistical Analysis Plan

61

 

9.6

Data Oversight

61

 

 

9.6.1

Central Review of Radiographs and DXA Scans

61

 

 

9.6.2

Data Safety Monitoring Board

61

10.0

ADMINISTRATIVE REQUIREMENTS

62

 

10.1

Good Clinical Practice

62

 

10.2

Ethical Considerations

62

 

10.3

Subject Information and Informed Consent

62

 

10.4

Protocol Compliance

62

 

Attachment 2, Attachment E-10

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

 

 

10.5

Case Report Form Completion

63

 

10.6

Source Documents

63

 

10.7

Study Monitoring

63

 

10.8

On-Site Audits

64

 

10.9

Drug Accountability

64

 

10.10

Record Retention

64

 

10.11

Study Termination

65

 

10.12

Liability and Insurance

65

11.0

USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

66

 

11.1

Use of Information

66

 

11.2

Publication

66

12.0

INVESTIGATOR AGREEMENT

67

13.0

REFERENCES

68

14.0

APPENDICES

70

 

14.1

Schedule of Visits and Procedures

71

 

14.2

Suggested Schedule of Events and Procedures by Study Visit

73

 

14.3

Body Mass Index Table

85

 

14.4

WHO (World Health Organization) Toxicity Criteria by Grade

86

 

14.5

Declaration of Helsinki

89

 

Attachment 2, Attachment E-11

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

 

LIST OF ABBREVIATIONS

 

Abbreviation

 

Term

°C

 

Degree celsius

°F

 

Degree fahrenheit

µg

 

Microgram

µL

 

Microliter

µmol

 

Micromole

AE

 

Adverse event

ALT

 

Alanine aminotransferase

ANOVA

 

Analysis of variance

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

FRAX

 

Tool developed by WHO to evaluate fracture risk of patients

FSH

 

Follicle-stimulating hormone

g

 

Gram

GCP

 

Good clinical practice

GGT

 

Gamma-glutamyltranspeptidase

GLP

 

Good laboratory practice

GMP

 

Good manufacturing practice

HEENT

 

Head, eye, ear, nose, and throat

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

 

Attachment 2, Attachment E-12

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

 

Abbreviation

 

Term

IVRS

 

Interactive voice response system

kg

 

Kilogram

L

 

Liter

LDH

 

Lactate dehydrogenase

MCH

 

Mean corpuscular hemoglobin

MCHC

 

Mean corpuscular hemoglobin concentration

MCV

 

Mean corpuscular volume

MedDRA

 

Medical dictionary for regulatory activities

mg

 

Milligram

mL

 

Milliliter

mmHg

 

Millimeter of mercury

msec

 

Millisecond

MTD

 

Maximal tolerated dose

N.P.O.

 

Nothing by mouth

ng

 

Nanogram

NOAEL

 

No observed adverse effect level

NSAID

 

Non-steroidal anti-inflammatory drug

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

PVCs

 

Premature ventricular complexes

QT

 

Total depolarization and repolarization time

QTc

 

Total depolarization and repolarization time corrected with heart rate

RBC

 

Red blood cell

rDNA

 

Recombinant deoxyribonucleic acid

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

WMA

 

World Medical Association

 

Attachment 2, Attachment E-13

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

 

INTRODUCTION

 

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 (2).  The common therapeutic approach
is to decrease bone loss with the use of antiresorptive agents such as
estrogens, selective estrogen receptor modulators (SERMs) and bisphosphonates
(3).  However, when osteoporosis is severe, these classes of pharmacological
agents provide only a moderate rate of return of bone mass and take a number of
years to effect their fracture reduction benefit.  A preferable approach is to
more rapidly reduce fracture risk by inducing a faster and greater return of
bone mass through use of bone anabolic agents.  To date, only one class of bone
anabolic drugs, PTH and its analogs, has been approved to prevent fractures in
postmenopausal women with osteoporosis who are at risk of fracture.  PTHrP, and
specifically BA058, offers another and potentially better therapeutic option
than PTH in this indication and shows particular potential for reversing bone
loss at the hip, the site of the most debilitating osteoporotic fractures in
elderly women.

 

Human parathyroid hormone (hPTH) is a naturally occurring 84-amino acid hormone
and is primarily a regulator of calcium homeostasis (4).  PTH acts directly on
bone to increase calcium resorption, on the gastrointestinal system to increase
calcium absorption, and on the kidney to increase calcium reabsorption and
1,25-dihydroxy Vitamin D production.  In turn, hPTH levels are tightly regulated
by Calcium and Vitamin D levels.  When present at high doses or when
administered in a continuous manner, hPTH has a catabolic effect on the skeleton
through its ability to activate and increase osteoclast number which leads to
increased serum calcium levels and decreased bone mass in humans (5).  However,
when given intermittently at low doses, hPTH has a well-documented anabolic
effect on bone, and can increase bone mineral density (BMD) in a number of
intact animal models as well as in osteoporotic patients (6).

 

The 34-amino acid terminal fragment of hPTH, known as hPTH(1-34), appears to
contain the full biological activity of native PTH(1-84) with regard to
restoration of bone (7).  Teriparatide (Forteo®/Forsteo®; Eli Lilly and Co.,
Indianapolis, Indiana), a recombinant human PTH (rhPTH(1-34)), was approved by
FDA in 2002 as a new therapy for osteoporosis.  Teriparatide can stimulate bone
formation, increase bone mass and reduce the risk of fractures in both animals
and humans (8).

 

Human PTH-related peptide (hPTHrP) is a member of the PTH family that is
secreted endogenously and which is partially homologous with the sequence of
hPTH at the amino-terminus, where 8 of the first 13 amino acids are identical in
both peptides (9).  Different to hPTH, PTHrP is produced by osteoblasts (10)
and, like hPTH, hPTHrP is also involved in calcium homeostasis (9) but to a
lesser degree than PTH.  PTHrP has also been shown to have an important role in
normal skeletal development (11), and has been shown to restore bone mass in
people when administered in an intermittent pattern (12).  When administered
daily for three months by subcutaneous injection to women with severe
postmenopausal

 

Attachment 2, Attachment E-14

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osteoporosis, PTHrP(1-36) in a dose of 6.6 µg/kg (approximately 400 µg/day)
increased lumbar spine BMD by 4.7%, a value that was statistically different
from placebo (1.4%).  In addition, there was no associated hypercalcemia
reported and no evidence of bone resorption when assessed by changes in serum
markers of bone resorption (12).

 

BA058 is a 34-amino acid analog of hPTHrP, with molecular modifications of
specific amino acids.  BA058 is expected to have similar or greater efficacy in
restoring BMD in individuals with osteoporosis than hPTH(1-34), but with less
risk of causing hypercalcemia.  Initial in vitro and in vivo studies identified
BA058 as displaying such properties (13-16).  Clinical evaluations have shown
BA058 to be well tolerated and to have significant positive effect on bone
formation.

 

Drug under Study

 

As noted above, BA058 is an analog of the first 34 amino acids of hPTHrP(1-34). 
BA058 was originally discovered and developed by the Beaufour-Ipsen Pharma Group
(Ipsen) under the names BIM44058 and BIM44058C.  Radius Health, Inc. (hereafter
referred to as RADIUS) acquired the license for the compound and is developing
BA058 to treat postmenopausal women with osteoporosis who are at high risk of
fracture.

 

Nonclinical pharmacology and toxicology studies have demonstrated that BA058 is
a potent and selective agonist of the human parathyroid hormone receptor 1
(hPTH1R).  It has significantly less calcium mobilizing activity at higher doses
than the native hormone and is a potent anabolic agent capable of fully
restoring BMD in ovariectomized, osteopenic rats.

 

Results from safety pharmacology studies indicate that BA058 is generally safe. 
The subcutaneous bioavailability was estimated to be 33% after administration of
a single dose of 10 µg/kg in rats.  Tachycardia and hypotension were observed in
dogs following both intravenous and subcutaneous administrations, however such
effects have not been observed in other species or in human studies.  Minor
pharmacological effects (increased bone formation, transient slightly higher
blood total calcium levels after dosing) were observed at low doses in the
toxicology studies.  The No Observed Adverse Effect Level (NOAEL) was 15, 25 and
25 µg/kg/day in rats in the 4-, 13, and 26-week studies, respectively, and 100,
50 and £ 10 µg/kg/day in monkeys in the 4-, 13- and 39-week studies,
respectively.  No local clinical signs or microscopic findings were noted at the
injection sites in rats and monkeys treated daily in the toxicity studies.  In
the 39-week study, minimal to moderate mineralization of lung and kidney was
observed at all doses evaluated.  There were slight but progressive and
occasionally significant changes in blood parameters.  Significant hypercalcemia
associated with premortem morbidity was also observed.  The repeated-dose
studies revealed the presence of specific antibodies against BA058 in a
proportion of animals tested, particularly following longer term exposure at
higher doses, and more commonly in monkeys than in rats.  The presence of
antibodies did not appear to neutralize the therapeutic effect of BA058.

 

To date, BA058 has been studied in single and multiple dose Phase 1 clinical
trials in which BA058 was evaluated in healthy male and female subjects.  In
addition, a Phase 2 dose

 

Attachment 2, Attachment E-15

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finding clinical study was performed in postmenopausal women with osteoporosis
to evaluate a range of doses of BA058.

 

The Phase 1 program involved 3 studies, a single-dose PK and bioavailability
clinical trial (Study 2-52-52127-001) that enrolled healthy male and female
subjects > 55 years of age, a repeated dose 7-day PK/PD study (Study
BA058-05-001) that enrolled 39 healthy postmenopausal women from 50 to 73 years
of age, and Study BA058-05-001B, a second repeated dose 7-day PK/PD study that
investigated a new liquid formulation of BA058 presented as a prefilled
multi-dose cartridge for use in a pen injector device.  The single exposure PK
study investigated subcutaneous doses of 5 mg to 120 mg.  The single exposure
study determined that BA058 was well-tolerated up to 80 mg, was 100%
bioavailable, had approximately dose-proportional kinetics, and had a half-life
of approximately 2.25 hours.  The repeated dose studies determined that BA058
was well-tolerated up to 100 mg, had limited hypercalcemic effect, induced early
changes in bone formation markers and that 100 mg was the maximal tolerated
dose.  Cardiac safety monitoring was conducted for all subjects in all BA058
Phase 1 studies and no clinically significant findings were identified.

 

A Phase 2 dose-finding clinical trial (Study BA058-05-002) was conducted in four
countries (the United States, Argentina, India, and the United Kingdom) to
evaluate the safety and efficacy of BA058 in women with osteoporosis (T-score £
-2.5).  This was a randomized, placebo- and comparator-controlled, parallel
group dose-finding study of BA058 to evaluate the effects of daily SC injections
of BA058 for six months in 225 postmenopausal women with osteoporosis,
subsequently extended to 12 months in a subset of patients.  Following
enrollment, patients underwent a 4-week Pretreatment Period of Calcium and
Vitamin D supplementation and instruction in study medication
self-administration, at the end of which patients were randomized to daily SC
self-administration of placebo, BA058 20 mg, 40 mg, 80 mg or teriparatide.

 

The study was powered for change from baseline in primary study endpoints: BMD
(spine) by DXA, and change in anabolic bone markers (serum PINP, BSAP, and
osteocalcin).  Other anatomical sites were also assessed by DXA for change in
BMD and additional anabolic and resorptive bone markers were also assessed. 
Routine clinical and laboratory safety assessments were employed with additional
monitoring of cardiac safety, serum calcium levels and local tolerance
assessment by patient diary.  Two hundred and seventy patients were enrolled
into pretreatment, 222 patients were randomized and 221 received study drug.  
One hundred and eighty-seven patients completed treatment and 155 patients were
evaluable as the Per Protocol Population.  The age of the study population
ranged from 54 to 84 years old (mean 65) and mean spinal T-score at screening
was -2.9.

 

Mean percent changes in total analyzable BMD of the spine at Week 24 increased
with BA058 dose (1.4%, 3.5%, 1.5%, and 2.9% in the placebo, BA058 20 mg, BA058
40 mg, and BA058 80 mg groups, respectively) for the Per Protocol Population. 
The test for a linear trend (dose response) was statistically significant
(p<0.001).  Mean percent change in the teriparatide group at this visit was
similar to the placebo group.  The anabolic bone markers showed a similar
statistically significant dose response.

 

Attachment 2, Attachment E-16

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Treatment emergent adverse events (TEAEs) were reported in 164 (74%) of the 221
patients through the End-of-Study visit (Week 28) and were similar in number and
profile across all treatment groups.  Treatment emergent and unrelated serious
adverse events of bronchitis, ovarian cancer, and diverticulitis were reported
in 3 patients (1%) overall in the placebo, 20 mg and 80 mg groups, respectively.

 

Serum calcium levels were measured pre- and post-dose at multiple times through
the study and were higher throughout the study in the teriparatide study group. 
Episodes of hypercalcemia (both above normal at any time or above the alert
value) post-dose were more common in teriparatide patients.  Overall, 27% of
patients treated with BA058 80 mg and 53% of patients treated with teriparatide
had a serum calcium level above normal (³ 10.2 mg/mL) on one or more occasions,
while the corresponding results for post-dose calcium values of ³10.2 mg/mL were
17% and 48%, respectively.  In addition, 18% of patients treated with
BA058 80 mg and 40% of patients treated with teriparatide had a clinically
significant elevation of serum calcium level (³10.5 mg/mL) on one or more
occasions, while the corresponding results for post-dose calcium values of
³10.5 mg/mL were 11% and 40%, respectively.

 

Low titer anti-drug antibodies were reported in 17 patients after 6 months of
BA058 treatment. Of the 17 positive patients, 1 was in the placebo group, 2 were
in the BA058 20 µg group, 8 were in the BA058 40 µg group and 6 were in the
BA058 80 µg group.  There were no associated safety events and no attenuation of
treatment efficacy.  One antibody-positive patient in the BA058 for Injection 40
µg group was found to have evidence of neutralizing activity at 24 weeks.  The
patient did not appear to have any attenuation of drug efficacy, having a 9.3%
gain in total analyzable spine BMD at the Week 24 assessment.  Finally, there
were no clinically significant changes on intensive cardiac safety assessments
conducted in approximately 30% of patients.

 

Fifty-five patients continued into a second 6 months of treatment with their
original treatment assignment; 48 of these patients completed the additional
treatment period.  BMD continued to show time-dependent and dose-dependent
increases.  At the end of study, final spinal BMD was approximately 50% greater
in the BA058 80 µg dose group than teriparatide and hip and femoral neck BMD
were approximately 100% greater than teriparatide.  The second six months of
treatment did not uncover additional safety considerations; the overall percent
of patients experiencing a TEAE over 48 weeks of study treatment was 81% as
compared to 74% in the 24-week study exposure.  One additional unrelated SAE of
bilateral crural hernia was reported in the second 24 weeks of study conduct in
the BA058 80 mg group.

 

In conclusion, this study demonstrated that BA058 induces a substantial positive
dose- and time-dependent change in BMD at both spine and hip in women with
osteoporosis and achieves this benefit safely and with substantially less
hypercalcemic effect than teriparatide.

 

Across the studies conducted with BA058, BA058-related AEs were generally mild
and did not require discontinuation of treatment.  The most common AEs observed
in patients were influenza, nasopharyngitis, bronchitis, headache,
hypercalciuria, back pain and arthralgia.  Occasional events of changes in
orthostatic blood pressure were noted but were mild or

 

Attachment 2, Attachment E-17

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moderate and did not appear to be dose related.  Reported local tolerance
reactions were generally mild and resolved quickly, with redness being the most
commonly reported symptom.  Elevated calcium levels were observed in a subset of
patients to a lesser degree than that observed in patients treated with
teriparatide.

 

According to the FDA-approved labeling for teriparatide, AEs reported in
clinical trials were usually mild and generally did not require discontinuation
of therapy.  The most commonly reported adverse events were pain, arthralgia,
rhinitis, asthenia, nausea, dizziness, headache, hypertension, cough increased,
pharyngitis, constipation, dyspepsia, and diarrhea.  Transient episodes of
symptomatic orthostatic hypotension were observed infrequently.  In addition,
teriparatide caused osteosarcomas in long-term toxicology studies in rats but
the clinical relevance of this finding is unknown.

 

For additional details on potential AEs and precautions with the use of BA058,
please refer to the Investigator’s Brochure.

 

Study Rationale and Selection of Doses

 

Study Rationale

 

This study is designed as a randomized, double-blind, placebo-controlled,
comparative Phase 3 study of BA058 in the treatment of postmenopausal women with
severe osteoporosis and at risk of fracture.  The purpose of the study is to
evaluate the efficacy and safety of BA058 80 µg in the prevention of fracture in
otherwise healthy ambulatory postmenopausal women with severe osteoporosis.  The
dose chosen for this study is based on the safety and pharmacodynamic
information derived in study BA058-05-002 according to predetermined criteria
provided in the protocol.  The population to be studied is the recommended and
intended population for treatment, postmenopausal women with severe osteoporosis
(17-19).  Daily SC doses of BA058 80 µg, Placebo or teriparatide 20 µg will be
self-administered for 18 months (78 weeks) to patients randomized [equally] to
one of 3 treatment groups.

 

Study Design and Rationale for Placebo

 

This study is designed as a randomized, double-blind, parallel-group, clinical
trial.  There will be 3 treatment arms, one of which will be BA058 80 µg, one of
which will be a placebo to BA058 80 µg, the study drug, and one of which will be
teriparatide 20 µg.  Therefore, 2 of 3 patients treated will receive an active
treatment.  All subjects, regardless of treatment assignment, will receive
Calcium and Vitamin D supplements during the Pretreatment and Treatment Periods.

 

The study will be blinded up to the time of randomization and assignment of the
patient to treatment.  On opening of the assigned treatment, although patients
and study personnel will remain blinded to BA058 80 µg or Placebo, it will
become apparent to them whether a BA058-based treatment or teriparatide has been
assigned.  An independent blinded evaluator will review all study radiographs. 
A second blinded evaluator will confirm all findings. A Data Safety Monitoring
Board (DSMB) will monitor study safety.

 

Attachment 2, Attachment E-18

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

 

The total period of placebo exposure and therefore of potential delay of
specific treatment is 18 months.  Placebo is the usual and recommended
comparator for studies in this indication.  While the indication infers the
prevention of fractures with treatment, the actual benefit is a reduction in
fracture incidence in women at risk.  It is calculated that while fractures may
occur in patients both on active treatment and Placebo, it is estimated that
treatment will result in a relative reduction of fracture risk of approximately
60% over 18 months.

 

In the RADIUS Phase 2 study (Study BA058-05-002), patients randomized to placebo
and supplemented with Calcium and Vitamin D over their 6-12 months of study
participation demonstrated no overall reduction in spinal or hip BMD and
reported no fractures while on study treatment.  In addition, all Placebo
patients will be offered the opportunity to transition to an approved active
treatment (a bisphosphonate) for 24 months on completion of 18 months of study
participation or earlier if a clinical fracture occurs.

 

Study Population

 

The study population in this protocol is the population recommended by
Regulatory Authorities (17-19) for the clinical evaluation of PTH and PTH-like
drugs in this indication: postmenopausal women (50 to 85 years of age) who are
more than 5 years post menopause and whose menopause has been confirmed by an
elevated serum FSH and a BMD T-score of <-2.5 (2.5 SD below the population norm)
and > -5.0 at the lumbar spine or hip (femoral neck) by dual energy x-ray
absorptiometry (DXA) and radiological evidence of 2 or more mild or one or more
moderate lumbar or thoracic vertebral fractures, or history of low trauma
forearm, humerus, sacral, pelvic, hip, femoral, or tibial fracture within the
past 5 years.  However, postmenopausal women older than 65 who meet the above
fracture criteria but have a T-score < -2.0 and > -5.0 may be enrolled.  In
addition, women older than 65 who do not meet the fracture criteria may also be
enrolled if their T-score is <-3.0 and > -5.0.  Women who are intolerant of
bisphosphonates as outlined in exclusion criterion # 17 (Section 0) and meet the
above criteria will also be allowed to enroll.

 

Based on midpoint demographics of the proposed study population, the anticipated
10-year fracture rate in Study BA058-05-003 is estimated to fall within the
recommended ranges in the relevant guideline (CPMP/EWP/552/95 Rev.2) when
calculated using the FRAX assessment tool (http://www.shef.ac.uk/FRAX/).

 

A sample size of 622 patients per treatment arm provides 90% power at a
two-sided alpha of 0.05 to detect a difference of 4% between treatments,
assuming a vertebral fracture rate of 7% in placebo patients and 3% in BA058 80
µg for injection-treated patients when the large scale approximation of the
binomial method is employed.  This superiority assessment infers a relative risk
reduction of 57% and presupposes the availability of a pretreatment and
post-treatment radiological assessment.  To ensure a per protocol population of
622 patients, an overall sample size of 800 patients per treatment arm will be
recruited, anticipating that approximately 20% of

 

Attachment 2, Attachment E-19

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

 

patients may not have a second evaluable X-ray film available for analysis. 
Prior studies have demonstrated that approximately 20% of enrolled patients drop
out over the lengthy period of the study and a further proportion (10%) fail to
provide an evaluable End-of-Treatment X-ray, therefore a sample size of 800
patients per arm is proposed.

 

Selection of Endpoints

 

Bone remodeling is a constant process in the adult human skeleton and maintains
the integrity of the skeleton through a process of replacing old bone
(resorption) with new bone formation (anabolism).  Both cortical and trabecular
bone are involved in this process which needs to be in balance to maintain
normal bone density and strength (20).  In childhood, the balance favors bone
formation and, with aging, the process favors the resorptive component, causing
bone loss.  Assessments of this balance of formation and resorption can be
performed over the long-term by quantitative imaging of bone density. 
Consequences of bone loss are commonly observed as fracture in a severe
osteoporotic population.  An improvement in bone quality and quantity can reduce
the risk of existing and incidental fracture.  Therefore, while earlier studies
have demonstrated the benefit of BA058 for improvement in BMD in postmenopausal
women, this study will assess the relative efficacy and safety of BA058 80 µg
for prevention of new fractures in the same population but among the cohort of
patients with a history of fracture, or those who are at an increased risk of
fracture.  While all new fractures will be assessed, the relative short duration
of treatment anticipated with BA058 is unlikely to yield definitive evidence of
fracture prevention benefit at all anatomical sites, therefore the study is
designed to identify a statistically significant benefit on vertebral fracture.
 Non-vertebral fractures will be assessed as a secondary efficacy endpoint as
will BMD changes by DXA at spine, hip and femoral neck as additional indices of
bone anabolic benefit.

 

In addition to BMD by DXA, bone formation and resorption markers will also be
assessed over time (21).  The rise in the markers of bone formation indicates
restoration of lost bone, in particular the lost microarchitecture that places
osteoporotic women at an increased risk for fracture.  Increases in the
principal markers of bone formation: N-terminal propeptide of type I procollagen
(PINP),  osteocalcin, and bone-specific alkaline phosphatase (BSAP) are accepted
predictors of BMD change (21,22).  Serum C-telopeptides (CTX), a marker of bone
resorption and collagen breakdown, will also be measured in this study.  Markers
of anabolic effect and resorptive effect have become valuable tools in the
management of osteoporosis since they can provide early information on potential
treatment efficacy (23).

 

Selection of Dose

 

The BA058 dose to be studied in this Phase 3 trial has been previously studied
in the Phase 1 and Phase 2 clinical trials.  The dose chosen for this study is
based on the safety and pharmacodynamic information derived in study
BA058-05-002 according

 

Attachment 2, Attachment E-20

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

 

to predetermined criteria provided in the protocol. The 80 µg dose was the
maximum efficacy dose in the BA058 Phase 2 clinical program, was well tolerated
(refer to Section 0) and demonstrated a significant increase in mean lumbar
spine and mean femoral neck BMD when compared to Placebo.  This beneficial
effect was achieved safely and with substantially less hypercalcemia than
teriparatide.  Doses of up to 120 µg have been studied in the Phase 1 program
and 100 µg has been determined to be the maximum tolerated dose, due to patients
experiencing an increase in nausea and one discontinuation due to vomiting at
the 120 µg dose.

 

BA058 80 µg per day will be dosed by SC self-administered injection.  In
addition, a matching Placebo comparator will be employed in one treatment arm
and teriparatide will be employed as a reference drug and comparator for
secondary efficacy and safety outcomes.  All enrolled patients will also receive
Calcium (500-1000 mg) and Vitamin D (400-800 IU) supplementation, or a dose to
be determined by the Investigator and agreed by the Sponsor Medical Monitor,
according to the patient’s need, from the Pretreatment Period until the end of
the Treatment Period; it will be recommended to patients that they continue
these supplements through the Follow-up Period.  The treatment regimens are
summarized in the table in Section 0.

 

Attachment 2, Attachment E-21

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STUDY OBJECTIVES

 

The primary objective of this study is to determine the safety and efficacy of
BA058 80 µg when compared to Placebo for prevention of vertebral fracture in
otherwise healthy ambulatory postmenopausal women at risk of fracture from
severe osteoporosis.  The secondary objectives of this study are to determine
the safety and efficacy of BA058 80 µg when compared to Placebo for prevention
of non-vertebral fractures and for additional secondary efficacy outcomes (bone
mineral density of spine, hip and femoral neck) and safety (hypercalcemia) when
compared to teriparatide (Eli Lilly and Co.) in otherwise healthy ambulatory
postmenopausal women at risk of fracture from severe osteoporosis.

 

The specific objectives of this study are to:

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on lumbar spine, total hip, and femoral neck bone mineral
density (BMD) in otherwise healthy ambulatory postmenopausal women with severe
osteoporosis when compared to teriparatide.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of non-vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the overall safety and tolerability of 18 months of
treatment with BA058 80 µg, and specifically the number of patients with
hypercalcemic events, in otherwise healthy postmenopausal women with severe
osteoporosis when compared to teriparatide and Placebo.

 

·                  Provide additional evidence of bone safety through
histomorphometric assessment of bone biopsy samples in a subset of patients from
the BA058 80 µg and Placebo groups.

 

·                  Provide additional evidence of renal safety through
radiological assessment by CT scan of a subset of patients from the BA058 80 µg,
Placebo and teriparatide groups.

 

Attachment 2, Attachment E-22

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INVESTIGATIONAL PLAN

 

Overall Design and Study Plan

 

This is a randomized, double-blind, placebo-controlled, comparative Phase 3,
multicenter, international study to evaluate the efficacy and safety of
BA058 80 µg in the prevention of fracture in otherwise healthy ambulatory
postmenopausal women with severe osteoporosis.  Women who are postmenopausal for
> 5 years and are 50 years old to 85 years old (inclusive) with a bone mineral
density T-score < -2.5 and > -5.0 at the lumbar spine or hip (femoral neck) by
dual energy x-ray absorptiometry (DXA) and radiological evidence of 2 or more
mild or one or more moderate lumbar or thoracic vertebral fractures, or history
of low trauma forearm, humerus, sacral, pelvic, hip, femoral, or tibial fracture
within the past 5 years may be enrolled.  Postmenopausal women older than 65 who
meet the above fracture criteria but have a T-score < -2.0 and > -5.0 may be
enrolled.  Women older than 65 who do not meet the fracture criteria may also be
enrolled if their T-score is < -3.0 and > -5.0.

 

The study consists of a Screening Period (1-3 weeks), a Pretreatment Period (1
week), a Treatment Period (78 weeks) and a Follow-up Period (4 weeks).  The
duration and number of scheduled visits for each study period, and the study
medications being administered in each study period are summarized in the table
below.

 

Study
Period

 

Duration of
Study Period

 

Scheduled
Visits (#)

 

Active
Treatment

 

1.

Screening

 

1-3 weeks

 

1

 

None

 

2.

Pretreatment

 

1 week

 

1

 

Calcium, Vitamin D

 

3.

Treatment

 

78 weeks

 

7

 

Calcium, Vitamin D, Study Medication

 

4.

Follow-up

 

4 weeks

 

1

 

Calcium, Vitamin D

 

 

Total

 

84-86 weeks

 

10

 

 

 

 

The total duration of study participation for an individual patient is
approximately 84-86 weeks from the initial screening visit to final study
evaluations.  The total duration of dosing with active medication (or placebo)
is 18 months (78 weeks).

 

The 18-month treatment study will be followed by an Extension Study,
administered as a separate protocol. For patients who received BA058 80 µg in
Study BA058-05-003, the study will be comprised of 2 periods: a 6—month
extension of BA058 80 µg treatment to assess the continued safety and efficacy
of BA058 80 µg up to a total of 24 months.  The second study period will assess
both the retention of benefit of BA058 over 12 months following withdrawal of
treatment and will assess the benefit of adding a bisphosphonate to retain or
augment BMD benefit on completion of a course of BA058 treatment. Patients will
be randomized to one of these two treatment options on completion of BA058
exposure.

 

Placebo patients who complete 18 months of study participation or experience a
clinical fracture will be given the opportunity to receive treatment with a
bisphosphonate for 24 months.  Patients will receive standard-of-care management
including assessment of BMD during this period.

 

Attachment 2, Attachment E-23

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During the Screening Period, informed consent is obtained, eligibility for study
entry is assessed and screening evaluations are performed, including baseline
radiographic and DXA (hip and spine) assessments and baseline (routine) safety
laboratory tests including serum biochemistry and hematology, and ECG.

 

Patients who are eligible for the study on the basis of screening evaluations
will enter the Pretreatment Period of the study and will have baseline
assessments of 1,25-dihydroxy Vitamin D, serum markers of bone metabolism and
BA058 serum antibody levels.  Patients will be given daily Calcium and Vitamin D
supplements, which will continue until the end of the Treatment Period; it will
be recommended to patients that they continue these supplements through the
Follow-up Period.  In addition, patients will undergo training in self-injection
with the device to be employed for administration of BA058 80 µg or Placebo. 
Patients subsequently randomized to treatment with teriparitide will be trained
to use the teriparatide pen on Day 1 prior to the first injection.  Patients
with medically significant abnormalities, or any patient who experiences a
serious adverse event during the Screening or Pretreatment Periods, will be
excluded from further study participation and treatment.  At the end of the
Pretreatment Period, all patients who continue to meet the eligibility criteria
for the study will enter the Treatment Period.

 

Patients who remain eligible for study participation will be randomized on Day 1
to treatment with one of the 3 treatment regimens shown below.

 

Treatment
Regimen

 

Study Medication

 

Daily 
Dose (SC)

 

Calcium and 
Vitamin D*

 

Number of
Patients

 

1

 

BA058

 

80 µg

 

500–1000 mg/day and 400–800 IU/day

 

800

 

2

 

Placebo

 

—

 

as above

 

800

 

3

 

teriparatide

 

20 µg

 

as above

 

800

 

 

 

 

 

 

 

Total

 

2400

 

 

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

*or a dose determined by the Investigator and agreed by the Sponsor Medical
Monitor, according to the patients’s need.

 

Treatment will be blinded to patients and investigators until the time of
randomization and assignment of treatment.  Blinding will be maintained between
BA058 80 µg and Placebo, but not with regard to teriparatide.

 

During the Treatment Period, patients will self-administer a single subcutaneous
dose of study medication once a day.  Study procedures during this study period
will include the collection of x-rays and DXA scans to evaluate fractures and of
serum samples to assess serum markers of bone formation and resorption. A subset
of patients in the BA058 80 µg and Placebo treatment groups (up to 100 per group
to obtain 75 evaluable biopsies per treatment group) will be asked to undergo a
bone biopsy at the end of the Treatment Period.  A further subset of patients in
all 3 treatment groups (100 per treatment group) will be asked to undergo a
renal CT scan at the end of the Treatment Period.  Serum samples for evaluation
of study medication levels and anti-BA058 antibody formation will be drawn at
specified visits during the Treatment Period.  Monitoring for adverse events,
concomitant medications

 

Attachment 2, Attachment E-24

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and other safety assessments will be conducted throughout the course of the
study (Pretreatment through End-of Study).

 

During the month after the last dose of study medication has been administered
(Follow-up Period), it will be recommended to patients that they continue to
take Calcium and Vitamin D supplements until they return for an End-of-Study
Visit during which final clinical evaluations are performed.  Patients eligible
to continue in the Extension Study will not undergo the End-of-Study Visit and
will transition into the Extension Study during the Follow-up Period.

 

The maximum duration of study participation for an individual patient is
estimated as 20 months (86 weeks) from the initial screening visit to the
End-of-Study Visit.  Ten clinic visits are planned during the study; additional
visits may be scheduled for clinical laboratory retesting or to obtain
protocol-specified evaluations, if required.

 

Visit windows are allowed for flexibility in scheduling of study visits.  For
initial visits which are scheduled at shorter intervals, a ± 1 or ± 3 day window
is allowed.  For visits later in the study, which occur at longer intervals, a ±
7 day window is allowed.

 

Overall, the Screening and Pretreatment Periods must be completed within 28
days. The Treatment Period is 18 months.  Therefore, all patients are to receive
78 weeks of treatment.  The allowable windows for each study visit are provided
in Appendix 14.1 and Appendix 0.

 

A brief summary of each study period 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
0 (Suggested Schedule of Events and Procedures by Study Visit).  A suggested
order of procedure conduct is also provided in this schedule.

 

Screening Period

 

The purpose of the Screening Period is to verify that the patient’s medical
history and current status are consistent with the inclusion and exclusion
criteria (refer to Sections 0 and 0, respectively), to ascertain the patient’s
willingness to participate in the study, to obtain written informed consent and
to establish baselines for the physical and laboratory parameters to be followed
for the duration of the study.  Patients will undergo baseline radiographic
(lumbar and thoracic spine) and DXA (hip and lumbar spine) evaluations.  One
clinic visit (Visit 1) is scheduled during the Screening Period (Study Days -28
to -8).

 

Prior to entering the Screening Period, each potential study participant will
have a preliminary assessment of inclusion/exclusion criteria by the
investigator.  A complete description of the study will provided to each
potential participant and written informed consent will be obtained.  After
informed consent is obtained, the patient is entered into the Screening Period
and procedures are conducted according to the Schedule of Visits and Procedures
(refer to Appendix 14.1).  Data should be recorded for patients who fail to
complete screening or fail to meet study eligibility

 

Attachment 2, Attachment E-25

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criteria, including the reason for failure.  Patients who meet the study
requirements based upon the Screening Period assessments will enter the
Pretreatment Period.

 

Pretreatment Period

 

During the Pretreatment Period, one visit (Visit 2) is scheduled.  Patients will
have baseline evaluations performed as outlined in the Schedule of Visits and
Procedures (Appendix 14.1).

 

Patients will undergo baseline efficacy labs.  This study visit is to be
scheduled within 7 days prior to the anticipated first day of treatment to allow
confirmation of clinical laboratory test results and continued eligibility. 
Patients who have experienced a serious adverse event during the Pretreatment
Period will be terminated from the study.

 

Patients will undergo training on self-injection with the BA058 pen injector
device in anticipation of treatment assignment.  Teriparatide is a marketed
treatment; therefore, if the patient is subsequently randomized to teriparatide,
training will be done with the teriparatide pen after randomization but before
the first injection on Day 1 (Visit 3).  In addition, patients will be provided
with daily Calcium (500—1000 mg) and Vitamin D (400—800 IU) supplementation, or
a dose to be determined by Investigator and agreed upon by the Sponsor Medical
Monitor, according to the patient’s need, which will be continued until the end
of the Treatment Period; it will be recommended to patients that they continue
these supplements through the Follow-up Period.  Patients will be instructed to
take the supplements during the evening with or without food or as otherwise
instructed by the Investigator.  Only the daily doses of Calcium and Vitamin D
identified in the study protocol and determined by the Investigator may be taken
during the study.  Any patient unable to take the preparation of Calcium and
Vitamin D supplied may be recommended a different preparation of Calcium and
Vitamin D by the Investigator as long as the same daily dose of both Calcium and
Vitamin D is administered.

 

On completion of the Pretreatment period, eligible patients will enter the
Treatment Period.

 

Treatment Period

 

The Treatment Period starts on Day 1 and continues for 18 months (78 weeks). 
Patients are randomized to treatment on Day 1 and begin treatment the same day. 
A subset of 300 patients per group will have a wrist DXA scan, which will occur
after randomization to study drug and can occur anytime up to 24 hours after the
first injection.  Those patients who are randomized to treatment with
teriparatide will be trained with the teriparatide pen prior to the first
injection on Day 1.

 

A total of 7 clinic visits are scheduled during the Treatment Period (Visits
3-9); the final Treatment Period visit will be scheduled to occur one day after
the last dose of study medication.  Treatment will be daily, by self-injection. 
During the first 30 days

 

Attachment 2, Attachment E-26

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of treatment patients will record drug dose, site of injection and any local
reactions in a patient diary card.  Local tolerance will again be assessed
during a second 30-day period.  This second diary will be provided to the
patient either at the Month [9] (Visit 7) or will be forwarded later by mail, as
appropriate, for completion by the patient during the 30 days of treatment in
Month [11] of treatment.  The diary will be collected and reviewed with the
patient for treatment compliance and adverse events at the Month [1] (Visit 4)
and Month [12] (Visit 8) visits.  The patient will also maintain a diary
throughout the study to summarize all study drug administration on a weekly
basis.

 

Study patients will continue Calcium and Vitamin D supplementation during the
Treatment Period.

 

Safety will be assessed at each study visit during the Treatment Period. 
Efficacy assessments will include one evaluation by x-ray after 18 months of
treatment (End-of-Treatment, Visit 9) and evaluations of BMD by DXA after [6],
[12] and [18] months of treatment (Visits 6, 8 and 9).  Serum markers of bone
metabolism, BA058 antibody and BA058 serum levels will also be measured during
the Treatment Period.  Additionally, a subset of patients treated with
BA058 80 µg or Placebo (up to [100] per group to obtain [75] evaluable biopsies
per treatment group) will consent and have a bone biopsy performed between Visit
8 and the End-of-Treatment visit (Visit 9).  A further subset of 100 patients
per treatment group (BA058 80 µg, Placebo and teriparatide) will undergo a renal
CT scan at End-of-Treatment (Visit 9).  Procedures are to be performed according
to the Schedule of Visits and Procedures (Appendix 14.1).

 

Patients who discontinue from the study prior to completing the Treatment Period
will have all End-of-Treatment Visit evaluations performed as close to the time
a patient is permanently discontinued from treatment as possible.  If possible,
an End-of-Study Visit should also be scheduled one month after the last dose of
study medication was administered.

 

Follow-up Period

 

The Follow-up Period is the one month interval after the last dose of study
medication during which patients are followed for adverse events, including
clinically significant laboratory abnormalities.  At the end of the Follow-up
Period, patients will return to the clinic to undergo final study assessments
(End-of-Study Visit; Visit 10).  Patients will be recommended to continue their
Calcium and Vitamin D supplements until the End-of-Study Visit (Visit 10).

 

Any clinically significant adverse events occurring during the Follow-up Period
will be assessed and recorded at the End-of-Study Visit.  Any adverse event or
clinical laboratory abnormality recorded at this final visit will be monitored
until it has resolved or has become chronic or stable.

 

Attachment 2, Attachment E-27

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After the End-of-Study Visit, patients who received Placebo and completed 18
months of treatment, as well as patients who received Placebo or BA058 and were
withdrawn due to incident vertebral or non-vertebral fragility fracture, will be
given the opportunity to receive treatment with a bisphosphonate for 24 months. 
Patients will receive standard-of-care management, including assessment of BMD
benefit, during this period.

 

Patients eligible to continue in the Extension Study will not undergo the
End-of-Study Visit and will transition into the Extension Study during the
Follow-up Period.

 

SELECTION OF STUDY POPULATION

 

Number of Subjects

 

A sufficient number of otherwise healthy postmenopausal women aged 50 to 85 with
osteoporosis will be screened so that 2400 eligible patients qualify for the
study and are randomized.

 

For the purposes of this study, osteoporosis is defined as a BMD that is 2.5
standard deviations or more below the norm of the adult female population. 
Postmenopausal women older than 65 who meet the fracture criteria but have a
T-score < -2.0 and > -5.0 may be enrolled.  Additionally, women older than 65
who do not meet the fracture criteria may also be enrolled if their T-score is <
-3.0 and > -5.0.

 

The specific inclusion and exclusion criteria for enrolling patients in this
study are presented below in Sections 0 and 0, respectively.  Exceptions to
these criteria should occur infrequently and should be discussed in advance and
approved by the Sponsor Medical Monitor.  If the exception is agreed upon (rare)
and a patient is allowed to participate, the Sponsor Medical Monitor will send
confirmation to the study site acknowledging the exception.  The confirmation
form or letter must be kept with the study records. Minor variations from the
normal range in clinical laboratory test results (hematology, chemistry, and
urinalysis) are acceptable if they are determined to be not medically
significant by the Investigator in that they do not compromise patient safety or
the assessment of efficacy and are documented as such.  Any unexpected
clinically significant abnormality that would exclude the patient from
participation in the study may be retested once.  If the parameter is normal on
retest, the patient may be included in the study.

 

Inclusion Criteria

 

Patients must meet all of the following criteria to be eligible to participate
in this study.

 

1.                                      The patient is a healthy ambulatory
postmenopausal woman from 50 to 85 years of age (inclusive) with osteoporosis.

 

2.                                      The patient has been postmenopausal for
at least 5 years.  Postmenopausal status will be established by a history of
amenorrhea for at least 5 years and by an elevated serum follicle-stimulating
hormone (FSH) value of > 30 IU/L.

 

Attachment 2, Attachment E-28

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3.                                      The patient has a bone mineral density
T-score < -2.5 and > -5.0 at the lumbar spine (L1-L4) or hip (femoral neck) by
dual energy x-ray absorptiometry (DXA) and radiological evidence of 2 or more
mild or one or more moderate lumbar or thoracic vertebral fractures, or history
of low trauma forearm, humerus, sacral, pelvic, hip, femoral, or tibial fracture
within the past 5 years.  Postmenopausal women older than 65 who meet the above
fracture criteria but have a T-score < -2.0 and > -5.0 may be enrolled.  Women
older than 65 who do not meet the fracture criteria may be enrolled if their
T-score is £ -3.0 and > -5.0.

 

4.                                      The patient is in good general health as
determined by medical history and physical examination (including vital signs),
has a body mass index (BMI) of 18.5 to 33 (Appendix 0), inclusive, and is
without evidence of clinically significant abnormality in the opinion of the
Investigator.

 

5.                                      Any required concomitant medications
which are not excluded in Section 6.0 may be continued through the study.  Every
effort should be made to maintain the medication at a stable dose throughout the
study, subject to the Investigator’s medical judgment.

 

6.                                      The patient has serum calcium,
PTH(1-84), serum phosphorus and alkaline phosphatase values all within the
normal range during the Screening Period.  Any patient with an elevated alkaline
phosphatase value, and who meets all other entry criteria, would be required to
have a normal bone-specific alkaline phosphatase result to be enrolled.

 

7.                                      The patient has serum 25-hydroxy Vitamin
D values above 15 ng/mL and within 3 times the upper normal range.

 

8.                                      The patient’s resting 12-lead
electrocardiogram obtained during screening shows no clinically significant
abnormality and a QTc < 470 msec (Bazett’s correction).

 

9.                                      The patient’s systolic blood pressure is
> 100 and < 155 mmHg, diastolic blood pressure is > 40 and < 95 mmHg, and heart
rate is > 45 and < 100 bpm.

 

10.                               The patient has no clinically significant
abnormality of serum hemoglobin, hematocrit, WBC and platelets, or usual serum
biochemistry: electrolytes, renal function, liver function and serum proteins.

 

11.                               The patient has read, understood, and signed
the written informed consent form.

 

Exclusion Criteria

 

Patients with any of the following characteristics are not eligible to
participate in the study.

 

General exclusion criteria:

 

1.                                      History of more than 4 spine fractures,
mild or moderate, or any severe fractures.

 

2.                                      Presence of abnormalities of the lumbar
spine that would prohibit assessment of spinal bone mineral density, defined as
having at least 2 radiologically evaluable vertebrae within L1-L4.

 

Attachment 2, Attachment E-29

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

 

3.                                      Unevaluable hip BMD or patients who have
undergone bilateral hip replacement (unilateral hip replacement is acceptable).

 

4.                                      History of bone disorders (e.g., Paget’s
disease) other than postmenopausal osteoporosis.

 

5.                                      Unexplained elevation of serum alkaline
phosphatase.

 

6.                                      History of radiotherapy (radiation
therapy).

 

7.                                      History of chronic or recurrent renal,
hepatic, pulmonary, allergic, cardiovascular, gastrointestinal, endocrine,
central nervous system, hematologic or metabolic diseases, or immunologic,
emotional and/or psychiatric disturbances to a degree that would interfere with
the interpretation of study data or compromise the safety of the patient.

 

8.                                      History of Cushing’s disease,
hyperthyroidism, hypo- or hyperparathyroidism or malabsorptive syndromes within
the past year.

 

9.                                      History of significantly impaired renal
function (serum creatinine >177 µmol/L or >2.0 mg/dL).

 

10.                               History of any cancer within the past 5 years
(other than basal cell or squamous cancer of the skin).

 

11.                               History of osteosarcoma at any time.

 

12.                               History of nephrolithiasis or urolithiasis
within the past five years.

 

13.                               Decrease of 20 mmHg or more in systolic blood
pressure or 10 mmHg or more in diastolic blood pressure from supine to standing
(5 minutes lying and 3 minutes standing) and/or any symptomatic hypotension at
screening (24,25).

 

14.                               Patients known to be positive for Hepatitis B,
Hepatitis C, HIV-1 or HIV-2.  Testing is not required in the absence of clinical
signs and symptoms suggestive of HIV infection or acute or chronic hepatitis.

 

Medication-related exclusion criteria:

 

15.                               Known history of hypersensitivity to any of
the test materials or related compounds.

 

16.                               Prior treatment with PTH or PTHrP drugs,
including BA058.  Patients who previously screened for this study cannot be
rescreened and entered into the study.

 

17.                               Prior treatment with bisphosphonates*,
fluoride or strontium in the past five years or prior treatment with gallium
nitrate, or with as yet unapproved bone-acting investigational agents at any
time (26).

 

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

(*Patients who had a short course of bisphosphonate treatment (3 months or less)
and were intolerant of the treatment are not excluded from study participation.)

 

18.                               Prior treatment with denosumab, calcitonin,
SERMs (such as raloxifene or tamoxifen), tibolone, or anabolic steroids in the
past 12 months. Estrogens

 

Attachment 2, Attachment E-30

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

 

administered as hormone replacement therapy (HRT), with or without progestins,
are not exclusionary.

 

19.                               Treatment with thiazide diuretics during the 7
days prior to the Screening Period, or ongoing treatment with thiazide
diuretics.

 

20.                               Treatment with anticonvulsants or
anticoagulants within the 6 months prior to the Screening Period.

 

21.                               Daily treatment with oral, intranasal or
inhaled corticosteroids within the 12 months prior to the Screening Period.

 

22.                               Exposure to general anesthesia within the 12
weeks prior to the Screening Period.

 

23.                               Exposure to an investigational drug within the
12 months prior to the Screening Period.

 

Lifestyle-related exclusion criteria:

 

24.                               Abnormal nutritional status (abnormal diets,
excessive or unusual vitamin or herbal intakes, malabsorption, significant
recent weight change), Vitamin D intake of > [1200] IU/day or Vitamin A intake
of > [10,000] IU/day.

 

25.                               Patient is known to abuse alcohol or use
illegal drugs within 12 months of the Screening Period.

 

Withdrawal of Patients from the Study

 

Patients 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.

 

The Investigator must withdraw patients from the study for the following
reasons:

 

·             Continuing significant deterioration from baseline (>7%) of BMD at
spine or hip (after confirmation of the finding)

 

·             Hypercalcemia or hypercalciuria as described in Section 4.6;

 

·             Treatment-related SAEs;

 

·             Severe hypersensitivity to BA058 or teriparatide;

 

·             Refusal of treatment;

 

·             Inability to complete study procedures;

 

·             Lost to follow-up.

 

The Investigator also has the right to withdraw patients from the study for any
of the following reasons:

 

·             WHO Grade 3 or 4 adverse events [Refer to Appendix 0];

 

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

 

Attachment 2, Attachment E-31

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

 

·             Serious intercurrent illness;

 

·             Non-compliance;

 

·             Protocol violations;

 

·             Administrative reasons.

 

Patients will be offered the opportunity to discontinue from the study for the
following reasons after site consultation with the Study Medical Monitor:

 

·             Incident vertebral or non-vertebral fragility fracture

 

If a patient is withdrawn or discontinued from the study, the reason for
withdrawal from the study is to be recorded in the source documents and on the
case report form.  All patients withdrawn prior to completing the study should
be encouraged to complete study procedures scheduled for the End-of-Treatment
and End-of-Study Visits.  The End-of-Treatment procedures should be conducted as
close to the time a patient is permanently discontinued from treatment.  If
possible, the End-of-Study Visit should be scheduled one month after the last
dose of study medication was administered.  All adverse events should be
followed as described in Section 0.

 

Patients treated with BA058 or Placebo who withdraw due to incident vertebral or
non-vertebral fragility fracture will be offered standard-of-care treatment with
a bisphosphonate for 24 months.

 

Temporary Suspension of Treatment

 

The investigator has the right to suspend treatment with study medication for up
to 14 continuous days or 28 cumulative days, without withdrawal of the patient
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 case report form and in source documents. 
Such patients should not be unblinded as to study medication. When treatment is
restarted, the patient should resume treatment with the next scheduled dose and
continue until the scheduled End-of-Treatment.

 

If the treatment suspension is due to a medical emergency and study medication
needs to be unblinded, please refer to Section 0 for the procedures to be
followed.

 

Response to Hypercalcemia or Hypercalciuria

 

Patients who develop hypercalcemia or hypercalciuria during the study are to
have treatment with study medication reduced or study medication temporarily
suspended as described below.

 

Attachment 2, Attachment E-32

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

 

Treatment Suspension due to Hypercalcemia

 

For any serum calcium value which is >0.3 to 1.0 mg/dL above the upper limit of
normal (ULN) (inclusive), confirm hypercalcemia by drawing a new serum sample as
soon as the result is received:

 

·                  If the result of the retest remains within this range,
discontinue Calcium and Vitamin D supplements for 7 days and perform a second
retest.  The patient is to continue study medication administration during this
interval.

 

·                  If the second retest is normal, the patient may continue on
study and resume Calcium and Vitamin D supplements.

 

·                  If the second retest is still elevated and the patient is
receiving BA058/Placebo, the patient continues on study with a dose reduction
for BA058 from 80 µg to 40 µg, but without Calcium and Vitamin D supplements.

 

·                  If the second retest is still elevated and the patient is
receiving teriparatide, the patient is to be discontinued from the study.

 

·                  If the patient continues in the study (with Calcium and
Vitamin D supplements) and has a repeat episode of a serum calcium value >0.3 to
1.0 mg/dL above the ULN (inclusive), repeat the above assessment.

 

·                  If the patient again returns to normal when not taking
Calcium and Vitamin D supplements, the patient may continue in the study without
Calcium and Vitamin D supplements.

 

·                  If the hypercalcemia is confirmed in the absence of Calcium
and Vitamin D supplements and the patient is receiving BA058/Placebo, the
patient continues on study with a dose reduction for BA058 from 80 µg to 40 µg,
but without Calcium and Vitamin D supplements.

 

·                  If the hypercalcemia is confirmed in the absence of Calcium
and Vitamin D supplements and the patient is receiving teriparatide, the patient
is to be discontinued from the study.

 

·                  If a BA058/Placebo patient continues on the study at the
reduced dose of 40 µg (without Calcium and Vitamin D supplements) and has
another episode of a serum calcium value >0.3 to 1.0 mg/dL above the ULN
(inclusive), perform a retest.

 

·                  If the retest is normal, the patient may continue on study at
the reduced dose (without Calcium and Vitamin D supplements).

 

·                  If the retest is still elevated, the patient is to be
discontinued from the study.

 

Attachment 2, Attachment E-33

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

 

For any serum calcium value >1.0 mg/dL above ULN:

 

·                  Discontinue Calcium and Vitamin D supplements and discontinue
the study medication as soon as the result is received.  Confirm hypercalcemia
by drawing a new serum sample as soon as possible.

 

·                  If the result of the retest remains >1.0 mg/dL above ULN,
perform a second retest after 3 days without Calcium and Vitamin D supplements
and study medication.

 

·                  If the second retest is normal, the patient may continue on
study and resume study medication and Calcium and Vitamin D supplements.

 

·                  If the second retest remains elevated (>0.3 mg/dL above ULN)
and the patient is receiving BA058/Placebo, the patient continues on study with
a dose reduction for BA058 from 80 µg to 40 µg, but without Calcium and Vitamin
D supplements.

 

·                  If the second retest remains elevated (>0.3 mg/dL above ULN)
and the patient is receiving teriparatide, the patient is to be discontinued
from the study.

 

·                  If a BA058/Placebo patient continues on the study at the
reduced dose of 40 µg (without Calcium and Vitamin D supplements) and has
another episode of a serum calcium value >0.3 mg/dL above the ULN, perform a
retest.

 

·                  If the retest is normal, the patient may continue on study at
the reduced dose (without Calcium and Vitamin D supplements).

 

·                  If the retest is still elevated, the patient is to be
discontinued from the study.

 

If the patient continues in the study and has a repeat episode of serum calcium
>1.0 mg/dL above ULN, the patient is to be discontinued from the study.

 

Treatment Suspension due to Hypercalciuria

 

For a Calcium:Creatinine ratio >0.4 mg/mg, check the patient’s serum calcium and
apply the algorithm outlined in Section 4.5.1 if Calcium is elevated.

 

If the Calcium:Creatinine ratio is >0.4 mg/mg and the serum calcium is normal:

 

·                  Discontinue Calcium and Vitamin D supplements and recheck
urine Calcium:Creatinine values after 7 days.

 

·                  If the urine Calcium:Creatine ratio continues to be >0.4
mg/mg in the presence of normal serum calcium, the patient may continue in the
study under medical supervision.

 

Attachment 2, Attachment E-34

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

 

·                  If the urine Calcium:Creatine ratio returns to normal, the
patient may restart Calcium and Vitamin D supplements and continue in the study.

 

If the patient restarts the Calcium and Vitamin D supplements and hypercalciuria
returns, Calcium and Vitamin D supplementation should be terminated.  The
patient may continue in the study under medical supervision.

 

Therefore, patients with hypercalciuria will not be discontinued from the study
in the absence of hypercalcemia except at the discretion of the Investigator.

 

Replacement of Patients

 

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

 

Attachment 2, Attachment E-35

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STUDY TREATMENTS

 

Study Medications

 

All study medications are for investigational use only and are to be used only
within the context of this study.  The Sponsor will supply all study
medications.

 

BA058 80 µg, Placebo and Teriparatide

 

BA058 80 µg, Placebo and teriparatide will be supplied by the Sponsor.  Pen
devices and needles for administration of study medications also will be
supplied to the study sites.

 

BA058 80 µg for Injection:  Each multi-dose cartridge contains 2 mg/mL BA058
(free base) in 5 mg/mL tri-hydrate sodium acetate and 5 mg/mL of phenol
(preservative) adjusted at pH 5.1 with acetic acid.  BA058 80 µg is supplied as
a liquid in a 1.5 mL Type 1 glass cartridge and is stored refrigerated at 5 ±
3ºC.  The multi-dose cartridge is designed to deliver a dose of 80 µg of BA058
in 40 µL of fluid when inserted into the Pen Injector device.  The pen is also
capable of delivering a half dose of BA058, or 40 µg of BA058 in 20 µL of fluid,
with appropriate manual adjustment.  When in use, multi-dose cartridges of
BA058 80 µg can be stored for up to 30 days at room temperature.  When used with
the supplied pen and needles, each cartridge may be used to deliver study
medication at the required daily dose for 30 days.  Patients will be provided
with a sufficient number of cartridges to continue on treatment until the next
scheduled return to the study site.

 

Placebo:  Placebo is formulated similarly but without active BA058 and is
similarly supplied as a liquid in a 1.5 mL Type 1 glass cartridge and is stored
refrigerated at 5 ± 3ºC.  The multi-dose cartridge is designed to deliver a dose
of Placebo in 40 µL of fluid when inserted into the Pen Injector device.  The
pen is also capable of delivering a half dose of 20 µL with appropriate manual
adjustment.  When in use, multi-dose cartridges of Placebo can be stored for up
to 30 days at room temperature.  When used with the supplied pen and needles,
each cartridge may be used to deliver study medication at the required daily
dose for 30 days.  Patients will be provided with a sufficient number of
cartridges to continue on treatment until the next scheduled return to the study
site.

 

Teriparatide (rDNA origin) injection (250 µg/mL) will be supplied in multi-dose
disposable pens containing a glass cartridge.  Each pen contains enough study
medication to deliver the required daily dose for 28 days.  Patients will be
provided with a sufficient number of pens to continue on treatment until the
next scheduled return to the study site.

 

Calcium and Vitamin D Supplements

 

Calcium and Vitamin D supplements will be provided by the sites.

 

Attachment 2, Attachment E-36

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Packaging, Labeling and Storage

 

Packaging

 

BA058 80 µg and Placebo will be supplied and packaged as identical cartridges
and pens.  The study will not be blinded with regard to teriparatide which is
supplied from marketed product; however, because teriparatide will be supplied
to the site in identical outer packaging as BA058 80 µg and Placebo, the site
will remain blinded until treatment is assigned, the package is opened, and its
contents are dispensed.  All packaging operations will be performed in
accordance with Good Manufacturing Practices.

 

Calcium and Vitamin D supplements will be provided as packaged by the
manufacturer.

 

Labeling

 

Each study medication kit will be labeled with an identifying kit number.  In
addition, each kit will be labeled with a caution statement and other
information required by local Regulatory Authorities.

 

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

 

Storage

 

All study medications (BA058 80 µg, Placebo, teriparatide) must be kept in a
secure, limited-access storage area at 2° to 8°C (36° to 46°F) until dispensed
for use to a study patient or until returned to the Sponsor.  Once dispensed,
BA058 80 µg or Placebo is stable for 30 days at room temperature.  When more
than one cartridge of BA058 80 µg or Placebo is dispensed for 30 days of use
each, it is recommended that the cartridges not in use be kept refrigerated
until required.

 

The teriparatide pen should be stored under refrigeration at 2° to 8°C (36° to
46°F) at all times.

 

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

 

Treatment Assignment

 

All patients who are screened for the study will be assigned a unique 7 digit
patient number which will be used to identify patients throughout the study and
on the CRFs.  Patient numbers will be assigned as follows:

 

XXX YYYY, where:

 

·             XXX represents the study site number;

 

·             YYYY represents the patient ID number

 

Patients who meet all inclusion criteria and none of the exclusion criteria and
successfully complete the Screening and Pretreatment Periods of the study will
be assigned sequentially to

 

Attachment 2, Attachment E-37

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a randomized treatment group on Day 1 of the Treatment Period.  Patients will
only receive one study ID at the time of screening and therefore will not
receive a new identifier at randomization.  During the randomization call, sites
will enter the kit number assigned to the subject into the IVRS system.  The
IVRS system will record the site number, the subject number and the
kit/randomization number within the system.  Information regarding treatment
assignment will reside within the IVRS system, as part of the study blinding.

 

Study medication kits will be assigned sequential numbers beginning with 001. 
The study medication kit number assigned to an eligible patient will be recorded
in the source documents, on the appropriate page of the CRF, and reported to the
IVRS system as described above.  Once a kit has been assigned, it may not be
reused.

 

The Sponsor statistician will be responsible for overseeing the preparation of
the master randomization scheme that will be used to package study medication
into kits and for the IVRS system.

 

Study Medication Administration

 

Patients will self-administer study medication on a daily basis during the
Treatment Period.  The first self-administration is to occur at the study site
under observation.  On the days of clinic visits, study medication must be
administered in the clinic to accommodate pre-injection and post-injection
procedures; study personnel may administer the study medication.

 

Patients will be trained by study personnel during the Pretreatment Period to
self-inject study medication with the BA058/Placebo cartridge and pen device. 
Those patients who are subsequently randomized to teriparatide treatment on
Day 1 will be trained in the use of the teriparatide pen on Day 1.  If a patient
requires assistance with study medication administration, an individual (e.g., a
family member) who has been trained by study personnel may provide assistance.

 

Patients will be instructed by the study site to inspect the contents of their
study medication device before each injection.  If the cartridge or pen contents
are not clear and colorless, or if the contents contain particles, the patients
will be instructed not to use that cartridge or pen and to contact the study
site for further guidance.

 

Injections should be administered in the morning and preferably at the same time
each day.  All injections are to be given in the periumbilical region, rotating
the exact site of injection each day.  If it is deemed medically necessary by
the investigator for an injection to be administered at a site other than the
abdomen, the alternate site of injection is to be recorded and the reason for
the change documented in the medical chart.

 

On the first day of study medication administration, the patient should
self-inject while in a sitting or lying position at the study site and remain in
that position for approximately 5 minutes.  The patient is to remain under
observation for a minimum of 60 minutes.  An orthostatic blood pressure
measurement will be taken 60 minutes after the injection.  On the days when
blood sampling is required after study medication injection, the patient is to

 

Attachment 2, Attachment E-38

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remain in the vicinity of the clinic for the blood collections scheduled up to 4
hours post-injection.

 

BA058 80 µg and Placebo will be supplied in cartridges, each containing enough
study medication to deliver the required daily dose for 30 days. Patients are to
be instructed to change cartridges after 30 days, regardless of how much
medication is left in the initial cartridge. Teriparatide will be supplied as a
pre-filled pen, each with enough study medication for 28 days. Patients will be
instructed to use a new pen after each 28-day period. At each clinic visit
during the Treatment Period, the used BA058 80 µg or Placebo cartridges, but not
pen, or the used teriparatide pens should be returned and a sufficient number of
new cartridges or teriparatide pens are to be provided to last until the next
clinic visit or as needed to replenish drug supply. Compliance, adverse events,
and use of concomitant medications should be reviewed upon drug re-supply.

 

Treatment Compliance

 

In order to evaluate the safety, efficacy and tolerance of BA058 80 µg, it is
critical that patients comply with the treatment regimen to which they were
randomized and honor the schedule of visits and procedures required by the
study. Patient compliance will be ascertained by three methods: patient diaries,
cartridge accountability, and site-assessment of remaining drug content of
returned cartridges.

 

The location, date and time that each dose of study medication was administered
will be recorded in a patient diary for the first 30 days of treatment for
review at the Month1 (Visit 4), and for the 30 days of Month 11 for review at
the Month 12 (Visit 8) study visit, and entered in the appropriate case report
form. Weekly summaries of study drug administration will also be maintained by
the patient throughout the study. All doses of study medication are to be
self-administered or administered by an individual trained in giving the
injection (e.g., a family member). Study personnel may administer the injection
on days of clinic visits.

 

If a patient does not take all study medication (BA058 80 µg, Placebo,
teriparatide, Calcium and Vitamin D supplements), the reason for the missed
dosing is to be recorded in source documents and on the appropriate case report
form. During the Follow-up Period, it is recommended that patients continue
taking the Calcium and Vitamin D supplements, but treatment compliance will not
be assessed during this post-treatment period.

 

The residual volume of returned cartridges will be measured by the height of the
fluid column and recorded in source documents and on the appropriate case report
form by the site personnel when the cartridge is returned by the patient.

 

Unblinding of Study Medication

 

Medical Emergency

 

Breaking the study blind for a patient should be done only in the event of a
medical emergency where the identity of study medication is necessary to
appropriately treat the

 

Attachment 2, Attachment E-39

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patient. The Investigator may unblind the patient as to study medication through
the IVRS system. The IVRS system will automatically document and record any such
unblinding and notify the Sponsor Medical Monitor and the Study Safety Officer
of the unblinding. In addition, the Sponsor Medical Monitor and the Study Safety
Officer also have the ability to unblind the study medication in a medical
emergency.

 

If the Investigator determines that the medical event that resulted in
unblinding of the study medication is not treatment related (relationship is
documented as “none”; see Section 8.3 for definitions of relationship), the
patient may continue treatment and participation in the study, providing no more
than 14 days has elapsed since the last dose of study medication (refer to
Section 0 for details regarding temporary suspension of treatment).

 

If the patient discontinues from further treatment with study medication, they
should undergo the End-of-Treatment and End-of-Study procedures as outlined in
Section 7.0 and the Schedule of Visits and Procedures (Appendix 14.1).

 

CONCOMITANT MEDICATIONS

 

Concomitant Medications

 

Calcium (500-1000 mg/day) and Vitamin D (400-800 IU/day) supplements, or a dose
to be determined by Investigator and agreed upon by the Sponsor Medical Monitor
according to the patient’s need, are required to be administered daily from the
Pretreatment Period until the end of the Treatment Period. It is recommended
that patients continue taking these supplements through the Follow-up Period.
The doses and schedule of Calcium and Vitamin D supplements, which are part of
the study medication protocol, should be adhered to and not be changed other
than for medical necessity (Section 3.1.2). 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 patient 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. These
are to be recorded on the appropriate case report form. Patients 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 patient 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 patient’s medical record or source document and
transcribed into the case report form.

 

Attachment 2, Attachment E-40

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

 

Prohibited Medications

 

Patients cannot take any medications, including over-the-counter,
non-prescription medication, with the exception of those noted in Section 0,
within 72 hours prior to dosing on Day 1.

 

As outlined in the exclusion criteria (Section 0), patients who have been
treated with bisphosphonates, fluoride or strontium in the past five years or
received prior treatment with gallium nitrate, or with as yet unapproved
bone-acting investigational agents at any time are to be excluded from study
participation. Patients treated with a short course of bisphosphonates (3 months
or less) who were intolerant of the treatment may be considered for study
participation.

 

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.

 

In addition, patients are ineligible for the study if they have received general
anesthesia within 12 weeks or have an abnormal nutritional status (abnormal
diets, excessive or unusual vitamin or herbal intakes, malabsorption).

 

Patients are ineligible for the study if they require or are receiving thiazide
diuretics. The use of thiazide diuretics must be discontinued at least one week
prior to screening for study participation.

 

Patients are ineligible for the study if they require or have received
anticonvulsants or anticoagulants within 6 months of study participation.

 

Attachment 2, Attachment E-41

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STUDY ASSESSMENTS

 

The study protocol will consist of a Screening Period, a Pretreatment Period, a
Treatment Period and a Follow-up Period. During the Screening Period, patients
will be assessed to establish study eligibility and to collect baseline
measurements.

 

In the Pretreatment Period, patients will undergo baseline efficacy labs,
receive training in the techniques of self-injection with the BA058/Placebo pen
device, receive diary training and begin taking Calcium and Vitamin D
supplements.

 

The Treatment Period will begin with randomization. Patients randomized to
teriparatide treatment will be trained in the use of the teriparatide pen on
Day 1. During the Treatment Period, patients will continue to take Calcium and
Vitamin D supplements and will self-administer the assigned study medication.
Safety, efficacy and pharmacodynamic evaluations will be performed.

 

During the Follow-up Period (the one month interval after the completion of
study treatment) it is recommended that patients continue the daily
supplementation of Calcium and Vitamin D. This will culminate in an End-of-Study
Visit where final study evaluations are performed and the patient is terminated
from the study.

 

The assessments performed at each study visit are displayed in the Schedule of
Visits and Procedures in Appendix 14.1. Appendix 0 provides a more detailed
schedule of the study procedures by study visit with a suggested order of
procedure conduct. Day 1 is defined as the first date that study medication is
administered. All days prior to this point are designated with a ‘minus’ sign
(e.g., Day —2, Day —1).

 

Exact procedures for centrifuging, storage, and shipping of laboratory samples
will be detailed in a separate document. The actual time of each sample
collection will be recorded in the case report form.

 

Study-specific assessments are to be conducted only after the patient has
provided written informed consent to participate in this study. The study
assessments are described in more detail in Section 0 below.

 

Clinical Procedures/Assessments

 

Informed Consent

 

Signed informed consent is obtained before any study-specific procedures are
performed.

 

Medical History

 

A complete medical history and review of body systems along with demographic
data will be obtained for all patients during the Screening Period (Days —28 to
-8). Data to be recorded in the case report form include the patient’s gender,
race, date of birth,

 

Attachment 2, Attachment E-42

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

 

tobacco use history, alcohol and caffeine use, and use at any time of hormone
replacement therapy. Prior fracture history will also be recorded.

 

Physical Examination

 

A complete physical examination (general appearance, head/ears/eyes/nose/throat
[HEENT], lungs/chest, heart, abdomen, lymph nodes, musculoskeletal, and
extremities) will be performed during the Screening Period and at the
End-of-Treatment. Any treatment-related findings should be followed up at the
final study visit during the Follow-up Period (Visit 10).

 

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.

 

Vital Signs, Weight and Height

 

Vital signs (orthostatic blood pressure, body temperature (°C) and respiration
rate (breaths/minute)) are to be measured and recorded at each study visit.

 

All blood pressure assessments will be conducted as orthostatic measurements.
Blood pressure (mmHg; measured in the same arm 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. At Treatment Visits 3, 4, 5, 6, 7, and 8,
orthostatic blood pressure will be measured prior to injection and again 60
minutes after injection.

 

Height (cm) will be measured at Visit 1, 2 and 9. Height will be measured in the
standing position at the Pretreatment and End-of-Treatment visits using a
medical stadiometer and standardized procedures each time.

 

Weight (kg) will be measured at Visits 1, 8, 9 and 10.

 

Electrocardiogram

 

Twelve-lead supine electrocardiograms (ECGs) will be performed according to the
Schedule of Visits and Procedures. The following ECG parameters will be
recorded: rhythm, heart rate, PR interval, QRS duration and QT/QTc. ECGs will be
performed during the Screening Period (Visit 1), the Treatment Period (Visits
3-9), and the Follow-up Period (Visit 10). At Treatment Visits 3, 4, 5, 6, 7,
and 8, ECGs will be measured prior to injection and again 1 hour after
injection. More than one ECG may be performed per time-point.

 

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

 

Attachment 2, Attachment E-43

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

 

copies of the appropriate laboratory certifications and normal ranges for all
laboratory parameters to be performed by that laboratory.

 

Routine clinical laboratory tests will be assessed during the Screening,
Pretreatment and Treatment Periods until the End-of-Treatment Visit (Visit 9).
Bone-specific laboratory tests (serum calcium, PTH(1-84), and 25-hydroxy Vitamin
D) will be conducted during the Screening and Treatment Periods as outlined in
Appendix 14.1. Once eligibility has been confirmed, anabolic (PINP, osteocalcin,
and BSAP) and resorptive bone marker (CTX) and 1,25-dihydroxy Vitamin D will be
measured during the Pretreatment and Treatment Periods as outlined in Appendix
14.1. Urine Calcium:Creatinine ratio will be determined during the Treatment
Period at Visits 3, 4, 5, 6, 7, 8, and 9. Creatinine Clearance also will be
determined during the Treatment Period at Visits 3, 4, 5, 6, 7, 8, and 9. Serum
calcium will be measured at treatment Visits 1 and 3, 4, 5, 6, 7, 8, and 9. Four
hour post-dose serum calcium will be measured at treatment Visits 3, 4, 5, 6, 7,
and 8. Hypercalcemia and hypercalciuria are to be evaluated as described in
Sections 4.5.1 and 4.5.2, respectively. In addition, all clinically significant
laboratory abnormalities indicating an adverse event will be followed up by
repeat testing and further investigated according to the judgment of the
Investigator.

 

Clinical laboratory evaluations are to be performed according to the Schedule of
Visits and Procedures (Appendix 14.1). Specific tests to be run are described
below.

 

Note: blood and urinalysis 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 prior to injection of the study medication with the exception of blood
samples for BA058 post-injection drug levels and 4-hour post-injection calcium
levels. For the 24-hour urine collection, patients will be instructed to begin
the 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 patient. Routine urinalyses are to
be performed using samples freshly voided during the clinic visit.

 

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

 

 

 

 

Coagulation

·    Prothrombin time (PT)

 

 

·    Partial thromboplastin time (PTT)

 

 

Attachment 2, Attachment E-44

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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

 

Vitamin D

 

 

 

·    1, 25-dihydroxy Vitamin D level

 

 

·    25-hydroxy Vitamin D level

 

Urine

 

 

24-hr.

·    Calcium

 

Collection

·    Creatinine

 

 

 

 

Urinalysis

·    pH

 

 

·    Glucose

 

 

·    Protein

 

 

·    Ketones

 

 

·    Bilirubin

 

 

·    Blood

 

 

·    Urobilinogen

 

 

·    Specific gravity

 

 

·    Nitrite

 

 

·    Leukocytes

 

Urine microscopic examination will be done, if positive findings noted on
dipstick.

 

 

 

 

Endocrine Tests

 

 

 

·    PTH(1-84)

 

 

·    *Serum FSH

 

 

·    *Serum estradiol

 

 

Attachment 2, Attachment E-45

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

 

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

* Only performed during Screening Period.

 

Serum Markers of Bone Metabolism

 

Blood samples will be taken to measure efficacy-related markers of bone
metabolism during the Pretreatment Period and at specified visits during the
Treatment Period in a subset of 600 patients.

 

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 and collagen breakdown will be measured:

 

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

 

Clinical and Radiologic Evaluation of Fractures

 

To be eligible for randomization and entry into the Treatment Period, patients
must have radiological evidence of 2 or more mild or one or more moderate lumbar
or thoracic vertebral fractures, or history of low trauma forearm, humerus,
sacral, pelvic, hip, femoral, or tibial fracture within the past 5 years. Women
older than 65 who do not meet the fracture criteria may also be enrolled if
their T-score is < -3.0 and > -5.0.

 

All patients will have x-rays taken to document fractures of the spine, lumbar
and thoracic vertebrae. Patients will undergo antero-posterior and lateral
radiographs of the lumbar and thoracic spines during the Screening Period and at
the End-of-Treatment visit. However, in the event that qualifying lumbar or
thoracic vertebral x-rays have been obtained as a consequence of routine patient
care within 3 months prior to the Screening visit and comply with the study
x-ray procedures, such x-rays may be used for assessment of eligibility.

 

Patients will also be clinically evaluated for non-vertebral fractures (wrist,
hip, rib, etc) which 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, and fracture will be assessed according to the severity
scale of Genant (1). A second blinded radiologist will confirm the assessment of
the first reviewer for all patient 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. A standardized graded scale of
severity of the vertebral deformity will be provided for this assessment.

 

Attachment 2, Attachment E-46

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Fractures identified during the study will not be recorded as AEs unless the
patient is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the patient’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.

 

Bone Mineral Density

 

To be eligible for randomization and entry into the Treatment Period, each
patient must have a BMD T-score < -2.5 and > -5.0 at the lumbar spine or hip by
dual energy x-ray absorptiometry (DXA). Postmenopausal women older than 65 who
meet the fracture criteria but have a T-score < -2.0 and > -5.0 may be enrolled
as well as women older than 65 who do not meet the fracture criteria but who do
have a T-score <-3.0 and > -5.0.

 

All patients will have BMD measurements taken via DXA during the Screening
(Visit 1) and Pretreatment (Visit 2) Periods and during the Treatment Period
(Visits 6, 8 and 9). However, in the event that qualifying BMD scans have been
obtained as a consequence of routine patient care within 3 months prior to the
Screening visit and comply with the study DXA procedures, such scans may be used
for assessment of eligibility and need not be redone at Screening.

 

The initial DXA will be performed during the Screening Period and will be used
to determine eligibility for participation in the study in conjunction with the
radiological evaluations of fractures. The DXA is to be performed on the hip
(femoral neck) and spine (L1-L4) at this visit and a qualifying T-score from
either location can be used to determine eligibility. The spinal DXA is to be
taken in the postero-anterior projection with any subsequent spinal DXA to be
taken in the same projection. Patients who meet the entry criterion for BMD who
satisfy all other eligibility criteria, and who have no exclusionary findings,
will then be enrolled. On Day 1, a subset of 300 patients per group will have a
wrist DXA scan. BMD measurements by DXA will be repeated at the lumbar spine
(L1-L4), hip, and wrist during the Treatment Period (Visits 6, 8 and 9).

 

Details regarding the procedures for the conduct and processing of DXA scans
will be provided in separate instruction manual. Patient eligibility will be
determined based on local analysis of the BMD scan at the study site. The
Central Imaging CRO will subsequently confirm the acceptability of each DXA scan
with the study sites. If any scan is unacceptable for technical or other
reasons, a repeat scan must be completed as soon as possible. Investigators will
be blinded to the results of all follow-up DXA scan results throughout the study
unless a safety issue is identified by the independent radiologist.

 

If the independent radiologist identifies any patient who shows a continuing
significant deterioration from baseline (>7%) of BMD at spine or hip during the
study, the study physician will be notified, the assessment will be repeated
and, if confirmed, the patient will be discontinued from the study. The study
physician will

 

Attachment 2, Attachment E-47

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

 

make this determination on the basis of the centrally read DXA relative to the
baseline measurement in consultation with the Sponsor Medical Monitor. All such
instances will be communicated to the DSMB.

 

Quantitative Bone Histomorphometry Assessment

 

In a subset of patients receiving BA058 80 µg or Placebo (up to 100 per group to
obtain 75 evaluable biopsies per treatment group), bone biopsy of the iliac
crest will be performed between Visit 8 and the End-of-Treatment Visit (Visit 9)
for assessment of quantitative bone histomorphometry using a dual-labeling
procedure. Details regarding the procedures for the conduct and processing of
the bone biopsy will be provided in separate instruction manual. All bone
biopsies will be read at a central specialized facility. A separate consent form
will be obtained for those patients agreeing to undergo the biopsy procedure and
additional clinic visits will be scheduled, as required, to prepare for the bone
biopsy procedure between Visit 8 and Visit 9.

 

Renal assessment by CT Scan

 

In a subset of patients, (up to 100 per treatment group), a CT scan of the
kidneys will be performed at the End-of-Treatment Visit (Visit 9) to assess the
renal parenchyma and collecting system for renal calcification. Details
regarding the procedures for the conduct and processing of renal CT scans will
be provided in separate instruction manual. A separate consent form will be
obtained for patients participating in the procedure.

 

BA058 Serum Level and Antibody Assessments

 

Samples for measurement of serum levels of BA058 will be taken at Visits 3, 4,
5, 6, 8 and 9 during the Treatment Period as part of a Population PK assessment.
One peak level is to be drawn per patient per visit at the following varying
post-injection times: 10 minutes to 30 minutes; 30 minutes to 1 hour; 1 hour to
2 hours; 2 hours to 3 hours; 3 hours to 4 hours. These draw times are to be
randomized across Visits 3, 4, 5, 6, and 8. At the End-of-Treatment (Visit 9),
only a trough level will be measured. Patients randomized to teriparatide will
not have samples drawn for BA058 serum levels.

 

Samples for anti-BA058 antibody assessment will be obtained at Visit 3 (Day 1)
and Visit 9 during the Treatment Period. Any patients who show presence of
antibodies at End-of-Treatment will have additional time points tested to
determine first occurrence of antibody positivity.

 

Local Tolerance

 

Assessment of local tolerance will consist of a self-evaluation by the patient
of any dermal reaction to study medication injection during the first 30 days of
study treatment for review at the Month1 (Visit 4), and for the 30 days of Month
11 for

 

Attachment 2, Attachment E-48

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review at the Month 12 (Visit 8) study visit, and entered in the appropriate
case report form.  This second diary will be dispensed at the Month 9 (Visit 7)
or forwarded to the patient by mail, as appropriate.  Each injection site will
be graded twice, 1 hour and 24 hours after the injection was performed and
information will be recorded by the patient into the patient diary.  In
addition, at each study visit during the Treatment Period, the Investigator will
review and assess the injection sites for any evidence of dermal reaction.

 

Each injection site will be graded according to the following skin reaction
scale.

 

Redness

0 =                         none

1 =                         minimal erythema, barely perceptible

2 =                         definite erythema, readily visible, less than 1 inch
(2.54 cm) in diameter

3 =                         definite erythema, extensive, greater than 1 inch
(2.54 cm) in diameter

Swelling

0 =                         none

1 =                         minimal swelling, without elevation

2 =                         definite swelling, readily visible; elevation less
than 1 inch (2.54 cm) in diameter

3 =                         definite swelling, extensive, greater than 1 inch
(2.54 cm) in diameter

Pain

0 =                         none

1 =                         minimal pain

2 =                         moderate pain, similar to a paper cut

3 =                         severe pain, similar to a bee sting or greater

Tenderness

0 =                         none

1 =                         minimal tenderness to touch

2 =                         moderate tenderness, no withdrawal to touch

3 =                          severe tenderness, withdraws to touch

 

Any injection site reaction with a grade of 3 will continue to be evaluated and
recorded in the diary by the patient at 24 hour intervals until the symptom or
sign has resolved.  If any reactions are severe or persistent at any time during
the Study, the patient will be instructed to contact the Investigator.

 

Patient Diaries

 

As noted above in Section 7.1.13, a diary to record study drug administration
and local tolerance will be maintained by patients during two 30-day periods of
the study.

 

The first diary will be provided on Day 1 (the first day of study treatment) for
the patient to record the date, time and site of study medication injection and
to assess local tolerance using the scale described in Section 7.1.13.  Patients
will record the required information daily during the first 30 days of the
Treatment Period and at the Month 1 (Visit 4) clinic visit study personnel will
review the diary with the patient.

 

Attachment 2, Attachment E-49

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The Investigator will assess the information recorded by the patient for adverse
events.  The second diary will be dispensed at the Month 9 (Visit 7) or later
mailed to the patient, as appropriate, for completion by the patient for the 30
days of Month 11.  The diary will be collected and reviewed at the Month 12
(Visit 8) visit.  The diary data will be entered into the CRF, and any
abnormality or adverse event will be followed up with the patient.

 

In addition, a diary summarizing all study drug administration will also be
completed by the patient on a weekly basis.  The weekly diary will be maintained
by the patient throughout the study and will be reviewed at each visit.

 

Activity and Diet

 

Patients who qualify for enrollment in the study will have no restrictions
placed on their usual level of activity or on their usual diet.

 

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.  The Sponsor (or
its designee) has established Standard Operating Procedures (SOPs) in conformity
with regulatory requirements worldwide to ensure appropriate reporting of safety
information.  All clinical trials sponsored by the Sponsor will be conducted in
accordance with those procedures.

 

Definitions, Documentation, and Reporting

 

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.

 

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.

 

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·                                          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 it 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 patient or
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 inpatient
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.

 

Monitoring of Adverse Events and Period of Observation

 

All AEs will be monitored until they are resolved or have become chronic or
stable.  AEs will be recorded on the case report forms starting from the time of
patient entry into the Pretreatment Period (Visit 2) of the study until 30 days
after the last dose of study medication.  SAEs will be collected up to 30 days
after the last dose of study medication.  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.

 

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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.

 

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
patient is hospitalized, the fracture is complicated, or the Investigator
considers the fracture to be unrelated to the patient’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.

 

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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.

 

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Rules for Suspension of the Study

 

The study will be immediately suspended and no additional doses of study
medication will be administered if one or more patients develop any of the
following serious adverse events deemed to be possibly or probably attributable
to study medication by the Investigator and/or Sponsor Medical Monitor, based
upon close temporal relationship or other factors:

 

·                  Death,

 

·                  Serious anaphylaxis characterized by severe angioedema,
hypotension, shock, bronchospasm, hypoxia or respiratory distress,

 

·                  New development or discovery of osteosarcoma in humans.

 

The study will be suspended pending review and discussion of all appropriate
study data with local Regulatory Authorities.  The study will not be restarted
until all parties have agreed to the course of action to be taken, the IRBs and
Regulatory Authorities have been notified, and IRB approval is confirmed.

 

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STATISTICAL PROCEDURES

 

The purpose of this section is to outline prospectively the types of analyses
and presentations of data that will answer the study objectives outlined in the
protocol, and to explain how the data will be handled and analyzed, adhering to
commonly accepted standards and practices of biostatistical analysis in the
pharmaceutical industry.

 

The primary objective of this study is to determine the safety and efficacy of
BA058 80 µg when compared to a matching placebo (Placebo) for prevention of
vertebral fracture in otherwise healthy ambulatory postmenopausal women at risk
of fracture from severe osteoporosis.  The secondary objectives of this study
are to determine the safety and efficacy of BA058 80 µg when compared to Placebo
for prevention of non-vertebral fractures and change in vertical height. 
Additional secondary efficacy outcomes include BMD (spine, hip and femoral neck)
and safety (hypercalcemia) when compared to teriparatide in otherwise healthy
ambulatory postmenopausal women at risk of fracture from severe osteoporosis.

 

The specific objectives of this study are to:

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on lumbar spine, hip, and femoral neck bone mineral density
(BMD) in otherwise healthy ambulatory postmenopausal women with severe
osteoporosis when compared to teriparatide.

 

·                  Determine the comparative efficacy of 18 months of treatment
with BA058 80 µg on reduction of non-vertebral fracture incidence in otherwise
healthy ambulatory postmenopausal women at risk of fracture from severe
osteoporosis when compared with Placebo.

 

·                  Determine the overall safety and tolerability of 18 months of
treatment with BA058 80 µg, and specifically the number of patients with
hypercalcemic events, in otherwise healthy postmenopausal women with severe
osteoporosis when compared to teriparatide and Placebo.

 

·                  Provide additional evidence of bone safety through
histomorphometric assessment of bone biopsy samples in a subset of patients from
the BA058 80 µg and Placebo groups.

 

·                  Provide additional evidence of renal safety through
radiological assessment by CT scan of a subset of patients from the BA058 80 µg,
Placebo and teriparatide groups.

 

Sample Size

 

A sample size of 622 patients per treatment arm provides 90% power at a
two-sided alpha of 0.05 to detect a difference of 4% between treatments,
assuming a vertebral fracture rate of

 

Attachment 2, Attachment E-55

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7% in placebo patients and 3% in BA058 80 µg for injection-treated patients when
the large scale approximation of the binomial method is employed.  This
superiority assessment infers a relative risk reduction of 57% and presupposes
the availability of a pretreatment and post-treatment radiological assessment. 
This population analysis would therefore be considered a modified ITT and will
constitute the primary analysis population for this study.  To ensure an
analysis size of 622 patients, an overall sample size of 800 patients per
treatment arm will be recruited, anticipating that approximately 20% of patients
may not have a second evaluable X-ray film available for analysis.  Should the
projected fracture rate of 7% in placebo patients not be achieved, the sample
size retains greater than 90% power at an alpha of 0.05 to detect a 4%
difference between treatments based on placebo fracture incidence of 6% or 5%.

 

For statistically-powered secondary endpoint assessments, the sample size will
have more than 90% power (n=275) at a two-sided alpha of 0.05 to detect a 1.15
percent difference between BA058 and teriparatide for spinal BMD based on a
superiority hypothesis.  Similarly, for total analyzable hip BMD, the sample
size will provide more than 90% power (n=25) at a two-sided alpha of 0.05 to
detect a 2.45 percent difference between BA058 and teriparatide treatment effect
and to detect a 2.00 percent difference between BA058 and teriparatide for
femoral neck BMD (n=125) based on the same hypothesis.

 

For differences in the number of patients in the BA058 and teriparatide
treatment groups reporting one or more events of hypercalcemia, both above the
upper limit of normal and at a value of 0.3 mg/mL above the upper limit of
normal, the medically significant elevation, the study sample size will also
provide more than 90% power to detect such a difference using a two-sided alpha
of 0.05.

 

Additional and other secondary endpoints will also be satisfied by these study
sizes and will be included in the details provided in the Statistical Analysis
Plan (SAP).

 

Randomization, Stratification and Blinding

 

Patients who have signed informed consent, completed the Screening and
Pretreatment Periods, and are eligible for the study will be equally randomized
into the three treatment groups on Day 1 of the Treatment Period.  A balanced
randomized block assignment will be utilized to insure that an equal number of
patients are assigned to each treatment group after a pre-specified block size
has been achieved.

 

The Population PK sample timings will be randomized across visits for each
patient.

 

Subsets of the population will be randomized to undergo bone biopsies, renal CT
scans, serum bone markers and DXA’s to analyze wrist BMD in such a manner to
ensure equal representation throughout the study.

 

No stratification is planned in this study.

 

BA058 80 µg and Placebo study medications will be prepared in a blinded
fashion.  The study will not be blinded with regard to teriparatide which is
supplied from marketed product; however, because teriparatide will be supplied
to the site in identical outer

 

Attachment 2, Attachment E-56

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packaging as BA058 80 µg and Placebo, the site will remain blinded until
treatment is assigned, the package is opened, and its contents are dispensed. 
Therefore, teriparatide will not be blinded in use relative to BA058 80 µg or
Placebo.

 

Populations for Analysis

 

All analyses and data summaries will be presented for the Intent-to-Treat (ITT)
or Safety Population.  In addition key selected endpoints will also be analyzed
for the Per Protocol Population.

 

Safety Population

 

The Safety Population is comprised of all patients who receive one or more doses
of study medication.

 

Modified Intent-to-Treat Population

 

The Modified ITT Population includes all patients with Pretreatment and
End-of-Treatment evaluable radiologic assessments.

 

Per Protocol Population

 

The Per Protocol Population includes all patients who meet the study entry
criteria and provide complete data, are at least 90% compliant with study
treatment, and have no dose adjustments.

 

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 for primary and secondary
efficacy analyses using the safety population will be performed using last
observation carried forward and will be 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.

 

Statistical Methods

 

Baseline Comparisons

 

Baseline characteristics, medical history, physical examination, vital signs and
ECG, will be summarized using standard descriptive statistics by treatment
group.  Specific demographic and baseline parameters will be tested for overall
agreement (uniformity across treatment groups) using one-way ANOVA or Chi-square
tests as appropriate for the type of data and specified in the Statistical
Analysis Plan.

 

Efficacy Analysis

 

The primary efficacy endpoint will be the number of BA058-treated patients
showing new vertebral fractures at End-of-Treatment when compared to Placebo. 
New

 

Attachment 2, Attachment E-57

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incident vertebral fractures will be evaluated according to the method of Genant
(1).  This analysis will be performed using a Fisher’s Exact test on the
modified intent to treat population.

 

Secondary efficacy endpoints will be analyzed using a Fisher’s Exact test
(categorical variables) or analyses of covariance employing the baseline measure
as the covariate (continuous variable) on the modified intent to treat
population unless otherwise noted below.  For continuous variables, analyses
will be performed on the last available assessment for each variable.

 

A hierarchical approach to the following key secondary analyses will be
employed.  Secondary variables will be analyzed in the order below using
two-sided alphas of 0.05.  Once an alpha is obtained that is above 0.05, the
inferential analysis of secondary outcomes in the hierarchy will stop and no
further secondary inferential analyses of the hierarchical variables will take
place.

 

·                  The change in Spine BMD from baseline to End-of-Treatment in
BA058-treated patients when compared to teriparatide.

 

·                  The change in Total Hip BMD from baseline to End-of-Treatment
in BA058-treated patients when compared to teriparatide.

 

·                  The change in Femoral Neck BMD from baseline to
End-of-Treatment in BA058-treated patients when compared to teriparatide.

 

An additional key powered secondary efficacy analysis will be the assessment of
hypercalcemia.

 

·                  The difference in number of patients with hypercalcemia in
BA058-treated patients at End-of-Treatment when compared to teriparatide.

 

Additional non-hierarchical analyses will be employed on the following efficacy
parameters:

 

·                  The change in vertical height in patients treated with BA058
when compared to Placebo.

 

·                  The number of BA058-treated patients showing new
non-vertebral fractures at End-of-Treatment when compared to Placebo.

 

·                  The difference in severity of incident vertebral fractures in
BA058-treated patients at End-of-Treatment when compared to Placebo.  The
analysis will employ a Chi-Square approach as severity is assessed in multiple
grades.

 

·                  Kaplan-Meier estimates of fracture incidence over time by
treatment group.  Point estimates (differences in incidence) of absolute and
relative risk reduction (hazard ratio) and the corresponding 95% confidence
intervals will

 

Attachment 2, Attachment E-58

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be provided.  Data will be censored at the time of study termination for those
not experiencing a fracture.

 

·                  The number of teriparatide-treated patients showing new
vertebral fractures at End-of-Treatment when compared to Placebo.  New incident
vertebral fractures will be evaluated according to the method of Genant (1).
This analysis will be performed using a Fisher’s Exact test on the modified
intent to treat population with a two-sided alpha of 0.20.  As the study is not
statistically powered for the comparison of teriparatide to Placebo and alpha of
0.20 will be employed to claim a statistical difference.

 

·                  The change in distal 1/3 radius BMD from baseline to
End-of-Treatment in BA058-treated patients when compared to Placebo.

 

·                  The changes in serum PINP, bone-specific alkaline
phosphatase, osteocalcin and CTX across treatment.

 

Where any single parameter is analyzed against more than one comparator within
the three treatments, an adjustment for multiplicity will be employed as
specified in the Statistical Analysis Plan.

 

Analyses of continuous variables (e.g., change in BMD and height) will be
analyzed using the Safety Population with last observations carried forward as
noted in section 9.4.

 

In addition, efficacy analyses for patients who have a dose adjustment and
continue on the study at a reduced dose, data may be summarized and tabulated.

 

All specified endpoints will be summarized by treatment groups and study period
using standard descriptive statistics (N, mean, SD, median, minimum, maximum). 
Changes in serum markers of bone metabolism (PINP, bone-specific alkaline
phosphatase, osteocalcin, and CTX) will be analyzed using repeated measures
Analysis of Variance (ANOVA) with factors for treatment (treatment groups), time
(study period) and their interaction.

 

A population PK/PD analysis will be performed on samples for measurement of
serum levels of BA058.  The PK/PD analyses and exposure response modeling will
be described in a separate SAP and report and will generally follow the guidance
provided by FDA (Exposure-Response Relationships — Study Design, Data Analysis,
and Regulatory Applications, U.S. Department of Health and Human Services, Food
and Drug Administration, Center for Drug Evaluation and Research (CDER), Center
for Biologics Evaluation and Research (CBER), April 2003).

 

Additional exploratory analyses will be presented as either pre-planned or
post-hoc to complement the overall understanding of study results.

 

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Safety Analysis

 

All patients who receive at least one dose of study medication will be included
in the safety analysis that will be performed on the following parameters:

 

·                  Incidence and severity of AEs.  Dose and cumulative dose at
which the AE occurred will also be recorded.

 

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

 

·                  Frequency of hypercalcemia across treatment groups (see
Section 0)

 

·                  Bone histomorphometry as assessed by bone biopsy at
End-of-Treatment in a subset of BA058 and Placebo patients.

 

·                  Renal safety as assessed by serum and urine creatinine (all
patients) and renal CT scan (subset of patients) in all treatment groups.

 

Safety assessments for changes in physical examination, vital signs (systolic
and diastolic blood pressure plus heart rate), ECG (normal and abnormal), and
laboratory tests will be descriptively summarized by group and selected study
periods.  In addition laboratory tests will be classified as low range, normal
range, or high range and shift frequencies summarized between the Screening
Period and the End-of-Treatment Visit.  Concomitant medication classes will be
coded employing the WHO drug dictionary and summarized by number and percent of
patients using each class and preferred drug term by treatment group.  All
treatment emergent adverse events will be coded for body system, preferred term,
and lowest level term using MedDRA and the number (%) patients experiencing each
type of adverse event will be summarized by treatment group, cumulative dose,
relationship to treatment, and severity.  All serious adverse events (SAE) and
adverse events leading to study discontinuation will be listed and the number
(%) patients presented by treatment group.

 

All adverse events collected prior to the first injection will be separately
summarized in a fashion similar to the treatment emergent adverse events.

 

Adverse event rates will be compared across treatment groups with Chi-square
and/or Fisher’s Exact test provided there is sufficient frequency of events to
justify the testing.  In addition, 95% confidence intervals will be presented
for rate differences between Placebo and each active treatment group.

 

Interim Analysis

 

No interim analyses are planned for this study.

 

Attachment 2, Attachment E-60

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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.

 

Data Oversight

 

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 fracture will be assessed according to a set of pre-determined
criteria.  A second blinded radiologist will review the assessment of the first
reviewer for all patient 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 an objective, unbiased evaluation of the
critical eligibility criteria at screening and during the course of the study to
provide objective efficacy data to determine the treatment benefit as
demonstrated on the pertinent radiologic and clinical data associated with this
study.  Finally, all renal CT scans will also be evaluated centrally by a
blinded independent reviewer and confirmed by a second reviewer to ensure
unbiased assessment of the renal parenchyma and collecting system.

 

Data Safety Monitoring Board

 

The DSMB will be responsible for overseeing study safety during the course of
the trial.

 

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ADMINISTRATIVE REQUIREMENTS

 

Good Clinical Practice

 

This study will be conducted in accordance with the International Conference on
Harmonization (ICH) for Good Clinical Practice (GCP) (27) 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.

 

Ethical Considerations

 

The study will be conducted in accordance with ethical principles founded in the
Declaration of Helsinki (28).  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.

 

Subject Information and Informed Consent

 

Each subject (or a legally authorized representative) must give written informed
consent prior to any 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.

 

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

 

Attachment 2, Attachment E-62

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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,
email 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 discuss 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.

 

Case Report Form Completion

 

Paper and/or electronic case report forms (eCRFs) will be developed to collect
information obtained during this study.  It is the Investigator’s responsibility
to ensure that CRFs are completed for each subject enrolled in this study and
for the accuracy, completeness, legibility and timeliness of the data reported
in each 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 CRF.

 

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

 

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.

 

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.

 

Attachment 2, Attachment E-63

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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.

 

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.

 

Drug Accountability

 

Accountability for the study medication at the study site is the responsibility
of the Investigator.  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
a pharmacist or other appropriately trained individual.

 

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 and according to the randomization
scheme.  Accountability records for all study medications will include dates,
quantities, batch/lot numbers, kit numbers, cartridge numbers, and patient
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 supplies must be inventoried, accounted for, and returned to
the Sponsor (or its designee), or if authorized, disposed of at the study site. 
Records of disposal must be maintained with the study records.

 

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 patient
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

 

Attachment 2, Attachment E-64

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

 

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.

 

Study Termination

 

This study may be terminated at any time, if in the opinion of the Sponsor, the
Investigator or the DSMB, 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).

 

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.

 

Attachment 2, Attachment E-65

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

 

USE OF INFORMATION AND PUBLICATION OF STUDY FINDINGS

 

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.

 

Publication

 

Results of this study may not be published prior to the completion of this study
and completion of the formal clinical study report and other required regulatory
reports and documents.

 

A single large publication of complete data from the study is planned.  It is
anticipated that the results of this study will be presented at scientific
meetings and/or published in a peer reviewed scientific or medical journal.  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.

 

Attachment 2, Attachment E-66

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

 

INVESTIGATOR AGREEMENT

 

To be completed by the Investigator

 

I have read Protocol BA058-05-003: A Randomized, Double-blind,
Placebo-controlled, Comparative Phase 3 Multicenter Study to Evaluate the Safety
and Efficacy of BA058 for Injection for Prevention of Fracture in Ambulatory
Postmenopausal Women with Severe Osteoporosis and at Risk of Fracture.

 

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 St.L. O’Dea. MB BCh BAO. FRCP(C)

 

Date

 

Attachment 2, Attachment E-67

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

 

REFERENCES

 

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

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

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

4.              Mannstadt M, Juppner H, and Gardella TJ. Receptors for PTH and
PTHrP: their biological importance and functional properties. Am J Physiol 1999;
277:F665-F675.

5.              Slovik DM, Neer RM, and Potts JT, Jr. Short-term effects of
synthetic human parathyroid hormone-(1-34) administration on bone mineral
metabolism in osteoporotic patients. J Clin Invest 1981; 68:1261-1271.

6.              Dempster DW, Cosman F, Parisien M, Shen V, and Lindsay R.
Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993; 14:690-709.

7.              Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster
JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, and Mitlak BH.
Effect of parathyroid hormone (1-34) on fractures and bone mineral density in
postmenopausal women with osteoporosis. N Engl J Med 2001; 344:1434-1441.

8.              Reeve J. Recombinant human parathyroid hormone. BMJ 2002;
324:435-436.

9.              Strewler GJ, Nissenson RA. Parathyroid Hormone-Related Protein.
In: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism.
Chapter 14, Fourth Edition. Philadelphia: Lippincott, Williams and Wilkins,
1999.

10.      Martin TJ. Osteoblast-derived PTHrP is a physiological regulator of
bone formation. J Clin Invest 2005; 115:2322-2324.

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

12.       Horwitz MJ, Tedesco MB, Gundberg C, Garcia-Ocana A, and Stewart AF.
Short-term, high-dose parathyroid hormone-related protein as a skeletal anabolic
agent for the treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab
2003; 88:569-575.

13.       Culler MD, Dong J, Shen Y, Taylor JE, Carlile L, Sullivan T, Batista
I, Bonin P, Carlson M, Lauer J, Savola A, Kasprzyk P, Morgan BA, Fisch C, Becret
A, Legrand J, and Woon CW. BIM44058, a novel analog of PTHrP with enhanced bone
building activity, but decreased calcium mobilization potential. Twenty third
Annual Meeting of the American Society of Bone and Mineral Research, Phoenix,
Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16
(suppl.1):S540.

14.       Legrand J, Guillaumat P, Forster R, Dong JZ, Woon CW, Claude J, and
Culler MD. BIM44058, a novel PTHrP analog, does not increase total plasma
calcium in cynomolgus monkeys at an effective pharmacological dose. Twenty third
Annual Meeting of the American Society of Bone and Mineral Research, Phoenix,
Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research 2001;16
(suppl.1):S539.

15.       Legrand J, Becret A, Fisch C, Attia M, de Jouffrey S, Dong JZ, Woon
CW, Claude J, and Culler MD. BIM44058, a novel PTHrP analog, increases bone
formation but not bone resorption histomorphometric parameters in old
ovariectomized osteopenic cynomolgus

 

Attachment 2, Attachment E-68

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

 

monkeys. Twenty third Annual Meeting of the American Society of Bone and Mineral
Research, Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and
Mineral Research 2001;16 (suppl.1):S539.

16.       Legrand J, Fisch C, Guillaumat P, de Jouffrey S, Dong JZ, Woon CW,
Claude J, and Culler MD. BIM44058, a novel PTHrP analog, restores in vivo spinal
bone mineral density in old ovariectomized osteopenic cynomolgus monkeys. Twenty
third Annual Meeting of the American Society of Bone and Mineral Research,
Phoenix, Arizona, USA, October 12-16, 2001. Journal of Bone and Mineral Research
2001;16 (suppl.1):S539.

17.       EMEA. Guideline on the evaluation of medicinal products in the
treatment of primary osteoporosis.2006.

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

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

20.      Martin TJ, Quinn JM, Gillespie MT, Ng KW, Karsdal MA, and Sims NA.
Mechanisms involved in skeletal anabolic therapies. Ann N Y Acad Sci 2006;
1068:458-470.

21.       Chen P, Satterwhite JH, Licata AA, Lewiecki EM, Sipos AA, Misurski DM,
and Wagman RB. Early changes in biochemical markers of bone formation predict
BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone
Miner Res 2005; 20:962-970.

22.       Bauer DC, Garnero P, Bilezikian JP, Greenspan SL, Ensrud KE, Rosen CJ,
Palermo L, and Black DM. Short-term changes in bone turnover markers and bone
mineral density response to parathyroid hormone in postmenopausal women with
osteoporosis. J Clin Endocrinol Metab 2006; 91:1370-1375.

23.       Delmas PD. Markers of bone turnover for monitoring treatment of
osteoporosis with antiresorptive drugs. Osteoporos Int 2000; 11 Suppl 6:S66-S76.

24.       Consensus statement on the definition of orthostatic hypotension, pure
autonomic failure, and multiple system atrophy. The Consensus Committee of the
American Autonomic Society and the American Academy of Neurology. Neurology
1996; 46:1470.

25.       Lipsitz LA. Orthostatic hypotension in the elderly. N Engl J Med 1989;
321:952-957.

26.       Black DM, Schwartz AV, Ensrud KE, Cauley JA, Levis S, Quandt SA,
Satterfield S, Wallace RB, Bauer DC, Palermo L, Wehren LE, Lombardi A, Santora
AC, and Cummings SR. Effects of continuing or stopping alendronate after 5 years
of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a
randomized trial. JAMA 2006; 296:2927-2938.

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

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

 

Attachment 2, Attachment E-69

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APPENDICES

 

Attachment 2, Attachment E-70

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

 

Schedule of Visits and Procedures

 

Study Period

 

Screening

 

Pretreatment

 

Treatment

 

Follow-up

 

 

Visit:

 

1

 

2

 

3

 

4

 

5

 

6

 

7

 

8

 

9

 

10

Procedure

 

Study Day/ Month:

 

-28 to –8

 

-7 to -1

 

D1

 

1

 

3

 

6

 

9

 

12

 

18

 

19

 

 

Visit Window (Days)

 

NA

 

NA

 

± 1

 

± 3

 

± 7

 

± 7

 

± 7

 

± 7

 

± 7

 

± 3

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Informed consent

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Review of entrance criteria

 

X

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Medical history

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Physical examination (1)

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

 

Vital signs, weight and height measurements (2), (3)

 

X

 

X

 

X(3)

 

X(3)

 

X(3)

 

X(3)

 

X(3)

 

X(3)

 

X

 

X

Electrocardiogram(4)

 

X

 

 

 

X(4)

 

X(4)

 

X(4)

 

X(4)

 

X(4)

 

X(4)

 

X

 

X

Urinalysis (dipstick) (5),(6)

 

X

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

Chemistry blood collection (6)

 

X

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

Hematology blood collection (6)

 

X

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

Coagulation (PT and PTT) blood collection (6)

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

 

FSH and serum estradiol (6)

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

PTH(1-84) (6)

 

X

 

 

 

 

 

 

 

 

 

X

 

 

 

X

 

X

 

 

25-hydroxy Vitamin D level (6)

 

X

 

 

 

 

 

X

 

 

 

X

 

 

 

X

 

X

 

 

1,25-dihydroxy Vitamin D level (6)

 

 

 

X

 

 

 

X

 

 

 

X

 

 

 

X

 

X

 

 

Serum markers of bone metabolism (6), (7)

 

 

 

X

 

 

 

 

 

 

 

X

 

 

 

X

 

X

 

 

BA058 antibody levels (6)

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

X

 

 

BA058 trough and peak (at randomized time) drug levels (8)

 

 

 

 

 

X(8)

 

X(8)

 

X(8)

 

X(8)

 

 

 

X(8)

 

X

 

 

Calcium (4 hour post-injection) (9)

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

 

 

 

24-hour urine collection (10) (for Calcium:Creatinine and Creatinine Clearance)

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

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

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

 

Bone mineral density of hip and spine by DXA (11)

 

X

 

 

 

 

 

 

 

 

 

X

 

 

 

X

 

X

 

 

Bone mineral density of wrist by DXA (11)

 

 

 

 

 

X

 

 

 

 

 

X

 

 

 

X

 

X

 

 

Renal CT Scan (in subset of patients)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

 

Quantitative Bone Histomorphometric Assessment (biopsy in subset of patients)
(12)

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

X

 

 

Calcium and Vitamin D supplements(13)

 

 

 

Daily Administration

Injection training for patients (14)

 

 

 

X

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Study medication kit assignment via IVRS

 

 

 

 

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Study medication administration (3)

 

 

 

 

 

Daily Administration (3)

 

 

Local tolerance (dermal reactions) assessment (15)

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

Patient diary review (16)

 

 

 

 

 

X

 

X

 

X

 

X

 

X

 

X

 

X

 

 

Document adverse events and concomitant medications

 

 

 

At any time; question patients at study visits

 

71

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14.1                        Schedule of Visits and Procedures (continued)

 

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

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

(2)                                 Vital signs (orthostatic blood pressure,
pulse rate, body temperature, and respiration rate) are to be recorded at each
study visit.
Height is to be measured at Visits 1, 2 and 9.  Height will be measured at
Visits 2 and 9 in the standing position using a medical stadiometer.
Weight is to be measured during the Screening Period, at Visit 8, at the
End-of-Treatment (Visit 9) and the Follow-up visit (Visit 10) only.
Orthostatic blood pressure is to be measured initially after 5 minutes in the
supine position and then again after standing for 3 minutes.

(3)                                 Study medication injections are to be
administered under supervision in the study clinic during scheduled clinic
visits.  Assessments of orthostatic blood pressure will be done pre-dose and 60
minutes post-dose at Visits 3, 4, 5, 6, 7, and 8.

(4)                                 ECGs are to be obtained pre-dose and 1 hour
post-dose on Visits 3, 4, 5, 6, 7 and 8.

(5)                                 On days of 24-hour urine collection, routine
urinalysis will be performed on a sample freshly voided during the clinic visit.

(6)                                 These blood and urine 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.  They are to be collected prior to
injection of the study medication during the Treatment Period.

(7)                                 Includes blood samples for PINP,
bone-specific alkaline phosphatase, serum osteocalcin and CTX (subset of 600
patients).

(8)                                 One peak level is to be drawn per patient
per visit at the following varying post-injection times:  10 minutes to 30
minutes; 30 minutes to 1 hour; 1 hour to 2 hours; 2 hours to 3 hours; 3 hours to
4 hours.  These draw times are to be randomized across Visits 3, 4, 5, 6, and 8.
At the End-of-Treatment (Visit 9), only a trough level will be measured.  No
BA058 serum levels will be drawn for patients randomized to teriparatide.

(9)                                 These samples are to be drawn
post-injection; the patient no longer needs to be fasting.  The patient is to
remain near the clinic for the post-injection blood collections.

(10)                          This urine collection will be used for urinary
calcium and urinary creatinine measurements.  Patients will discard the 1st void
and begin a 24-hour urine collection the day prior to the clinic visit.  If a
routine urinalysis is to be performed during the clinic visit, a separate sample
freshly voided during the clinic visit will be used.

(11)                          DXA is to be performed initially on the hip
(femoral neck) and spine (L1-L4) during the Screening visit.  A DXA of the wrist
should be performed in a subset of patients on Day 1.  Each DXA for a given
patient must be performed on the same machine, preferably by the same
technician.

(12)                          Patients who agree to undergo the quantitative
bone histomorphometric assessment will have additional clinic visits scheduled,
as required, to prepare for the bone biopsy performed between Visit 8 and the
End-of-Treatment visit (Visit 9).

(13)                          Calcium and Vitamin D supplements begin at the
Pretreatment Period visit and continue until the end of the Treatment Period; it
will be recommended to patients that they continue these supplements through the
Follow-up visit.  A supply of supplements is provided for each patient.  At each
study visit, the patient’s supply is to be assessed and the patient resupplied
as necessary.  Drug usage reconciliation is to be performed when a new supply is
provided.

(14)                          All patients will be trained on the use of the
BA058/Placebo cartridge/pen delivery device at Visit 2; patients who are
subsequently randomized to receive teriparatide will be trained on the use of
the teriparatide pen at Visit 3.

(15)                          The Investigator is to review and assess the
injection sites at each Treatment Period visit.

(16)                          Diaries will be provided to patients to record
information regarding study medication injections (date/time/site of injection;
local tolerance) for the first 30 days of treatment and for 30 days prior to
Month 12 (Visit 8). In addition, the patient will also maintain a diary
throughout the study to summarize all study drug administration on a weekly
basis. The diaries are to be reviewed with the patient at each study visit.

 

72

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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:

 

·                  During the Treatment Period, on the days of clinic visits,
study medication must be injected at the clinic to accommodate pre-injection and
post-injection procedures; study personnel may administer the study medication
on those days.

 

·                  Pre-injection procedures include assessments of the patient,
vital signs, ECG, and pre-injection blood/urinalysis collections.

 

·                  Pre-injection blood and urinalysis 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; post-injection blood samples do not
require fasting.

 

·                  BMD 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.  Patients 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.

 

·                  Pen devices and needles for administration of study
medications will be provided.  BA058 80 µg and Placebo will be supplied in
cartridges, each containing enough study medication to deliver the required
daily dose for 30 days.  Patients are to be instructed to change to a new
cartridge after 30 days, regardless of how much medication is left in the
cartridge.  At each clinic visit, the used BA058 80 µg or Placebo cartridges,
but not pen, are to be returned and a sufficient number of new cartridges to
last until the next clinic visit are to be provided.  Teriparatide will be
supplied as pre-filled pens, each with enough medication for 28 days.  At each
clinic visit, the used teriparatide pens should be returned and a sufficient
number of new pens provided to last until the next clinic visit.

 

·                  Patients 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 they are discharged from the study.  This
is required until the End-of-Treatment.  During the Follow-up Period it is
recommended that they continue the supplements.

 

·                  Patients will be approached at Visit 8 regarding
participation in the quantitative bone histomorphometric evaluations.  Patients
who consent to this assessment will undergo a bone biopsy between Visit 8 and
Visit 9.  Additional clinic visits will be scheduled to complete all necessary
preparations for the procedure.

 

73

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

 

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 patient regarding any new health issues

·                  Question patient regarding any new adverse events

·                  Question patient regarding any new concomitant medications

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

 

Vital Signs and Weight

 

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

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

·                  Respiration rate (breaths/minute)

·                  Body temperature (°C)

·                  Weight (kg)

 

Height

 

·                  At Visits 2 and 9 standing measurements (cm) are to be
performed using the same medical stadiometer and standardized procedures each
time.

 

ECG

 

·                  Twelve-lead supine electrocardiogram

·                  Print hard copy for reading by qualified study personnel

 

24 Hour Urine Collection

 

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

·                  Patient to collect urine for approximately 24 hours

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

·                  Process for calcium and creatinine

 

Urinalysis

 

·                  Obtain under fasting conditions (N.P.O. except water for 8
hours)

·                  Routine urinalysis is to be performed using a sample freshly
voided during the clinic visit.

 

Review study medication injection procedures with patient

 

·                  Injections should be given daily, preferably at the same time
each morning

·                  Injections are to be given in the periumbilical region,
rotating the exact site of injection each day to minimize discomfort

·                  If medically necessary for an injection to be administered at
a site other than the abdomen, the alternate site is to be recorded and the
reason is to be documented in the medical chart

·                  Patients are to self-inject study medication; if the patient
is unable to self-inject, she may be assisted by a competent companion (e.g.,
family member) trained to use the injection devices

·                  Study personnel may administer the study medication at clinic
visits

 

Scheduling and instructions for next clinic visit

 

·                  Schedule visit

·                  Remind patient of any fasting requirements

·                  Provide urine collection instructions as necessary

·                  Remind patient that injections are to be administered at the
clinic during Treatment Period study visits

 

Vitamins and Calcium Supplements

 

·                  Calcium and Vitamin D supplements begin during the
Pretreatment Period and continue until the end of the Treatment Period.  Only
those supplements supplied as part of study medication may be used and are to be
used at the daily recommended dose (see Section 3.1.2).

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

·                  Recommend to patients that they continue these supplements
through the Follow-up Visit.

·                  Dispense the initial supply of supplements for each patient
at Visit 2.

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

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

 

74

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SCREENING PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 1

 

-[28 ]to –[8]

 

Written informed consent

 

 

Screening Visit

 

 

 

·      Must be obtained before any study-specific procedure is performed

Review of entrance criteria

Medical history and concomitant medications

Physical exam

*Vital Signs and Weight and Height (stadiometer not necessary)

*ECG

Urinalysis — dipstick:  fasting conditions (N.P.O. except water for 8 hours)

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

·      Coagulation (PT and PTT)

·      FSH and serum estradiol

·      PTH(1-84)

·      25-hydroxy Vitamin D level

Clinical and Radiologic Fracture Evaluations

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

·      Document any non-vertebral fractures

Bone Mineral Density DXA

·      Perform hip (femoral neck) and spine (L1-L4) DXA

*Scheduling and Instructions for next Clinic Visit

Screen Failures:

·      Data for patients who do not successfully complete screening procedures
or do not meet study eligibility requirements should be entered into the eCRF,
including the reason for failure.

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

75

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

 

PRETREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 2

 

-7 to -1

 

 

*Recent Health Status

·      Document any changes from Visit 1 including changes in medical history,
including any new adverse events or concomitant medications

*Vital Signs

*Height (cm):  standing height measurement with medical stadiometer

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      1,25-dihydroxy Vitamin D levels

·      Serum markers of bone metabolism

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

Calcium and Vitamin D Supplements

·      Dispense supply of Calcium and Vitamin D supplements

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

*Training in Self-Injection

·      Instruct patient in use of the BA058/Placebo device

·      If patient is unable to self-inject, train competent companion (e.g.,
family member) to use the injection device

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

76

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

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 3

 

First Treatment Visit

 

1

(± 1 day)

 

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage.

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

·      Dispense study medication diary card for recording of date, time, site of
injection and local tolerance on a daily basis.

·      Dispense weekly patient diary.

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs

*ECG

*24 Hour Urine Collection and Urinalysis

Study medication kit assignment via IVRS:

·      Call IVRS system: provide patient screening number and DOB

Blood Collection

·      Chemistry

·      BA058 antibody sample (if a BA058 treatment is assigned)

Bone Mineral Density DXA in a subset of  patients

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Patients randomized to teriparatide are to be trained in injection
procedures

·      Observe/Assist patient with injection

·      patient should self-inject while in a sitting or lying position

·      patient should remain in that position for approx. 5 min.

·      Observe patient in clinic for a minimum of 60 minutes

·      Provide patient with study medication: 1 pen and cartridges for BA058 80
µg or Placebo; prefilled pen(s) for teriparatide.

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (1hour post-injection)

Blood Collection:  non-fasting

·      BA058 peak drug levels (at randomized time).  Only draw for patients
randomized to BA058, Placebo

·      Calcium (4 hours post-injection)

Local tolerance assessment

·      Remind patients to assess dermal reactions 1 and 24 hours post-injection

·      Investigator to review diary and assess injection sites

Calcium and Vitamin D Supplements

·      Assess patient’s supply of Calcium and Vitamin D supplements; resupply as
necessary

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

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 4

 

Month [1]

 

*Recent Health Status

 

77

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

 

 

After [1st]] Month of Treatment

 

(± 3 days)

 

 

·      Document any changes from last visit

Patient Review

·      Review  Calcium and Vitamin D supplement usage

·      Review diaries of study medication usage/injection site reactions

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

·      Dispense weekly patient diary, if needed

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

·      25-hydroxy Vitamin D level

·      1,25-dihydroxy Vitamin D levels

*24 Hour Urine Collection and Urinalysis

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Assist with drug injection as necessary

·      BA058 80 µg or Placebo: collect used cartridges; supply new cartridges as
necessary

·      Teriparatide: collect used pen; supply new pre-filled pens as necessary

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (60 minutes post-injection)

Blood Collection :  non-fasting

·      BA058 peak drug levels (at randomized time).  Only draw for patients
randomized to BA058, Placebo

·      Calcium (4 hours post-injection)

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

78

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

 

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 5

 

After [3] Months of Treatment

 

Month [3]

(± 7 days)

 

 

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage

·      Review study medication usage/injection site reactions

·      Review weekly patient diary

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

·      Dispense weekly patient diary, if needed

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

*24 Hour Urine Collection and Urinalysis

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Assist with drug injection as necessary

·      BA058 80 µg or Placebo: collect used cartridges; supply new cartridges as
necessary

·      Teriparatide: collect used pen; supply new pre-filled pens as necessary

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (60 minutes post-injection)

Blood Collection:  non-fasting

·      BA058 peak drug levels (at randomized time).  Only draw for patients
randomized to BA058, Placebo

·      Calcium (4 hours post-injection)

Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

79

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

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 6

 

After [6] Months of Treatment

 

Month [6]

(± 7 days)

 

 

 

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage

·      Review study medication usage/injection site reactions

·      Review weekly patient diary

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

·      Dispense weekly patient diary, if needed

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

·      PTH(1-84)

·      25-hydroxy Vitamin D levels

·      1, 25-dihydroxy Vitamin D levels

·      Serum markers of bone metabolism:

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

*24 Hour Urine Collection and Urinalysis

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Assist with drug injection as necessary

·      BA058 80 µg or Placebo: collect used cartridges; supply new cartridges as
necessary

·      Teriparatide: collect used pen; supply new pre-filled pens as necessary

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (60 minutes post-injection)

Blood Collection:  non-fasting

·      BA058 peak drug levels (at randomized time).  Only draw for patients
randomized to BA058, Placebo

·      Calcium (4 hours post-injection)

Bone Mineral Density

·      Perform hip (femoral neck), spine (L1-L4) and radius DXA.

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

80

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

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 7

 

After [9] Months of Treatment

 

 

Month [9]

(± 7 days)

 

 

 

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage

·      Review study medication usage/injection site reactions

·      Review weekly patient diary

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

·      Dispense study medication diary card for recording of date, time, site of
injection and local tolerance on a daily basis for the 30 days of Month 11. The
diary can also be sent later to the patients by post.

·      Dispense weekly patient diary, if needed

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

*24 Hour Urine Collection and Urinalysis

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Assist with drug injection as necessary

·      BA058 80 µg or Placebo: collect used cartridges; supply new cartridges as
necessary

·      Teriparatide: collect used pens; supply new pre-filled pens as necessary

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (60 minutes post-injection)

Blood Collection:  non-fasting

·      Calcium ([4] hours post-injection)

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

81

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

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 8

After [12] Months of Treatment

 

 

Month [12]

(± 7 days)

 

 

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage

·      Review diaries of study medication usage/injection site reactions

·      Dispense weekly patient diary, if needed

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

BEFORE STUDY MEDICATION ADMINISTRATION

*Vital Signs and Weight

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

·      PTH(1-84)

·      25-hydroxy Vitamin D levels

·      1, 25-dihydroxy Vitamin D levels

·      Serum markers of bone metabolism

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

*24 Hour Urine Collection and Urinalysis

 

STUDY MEDICATION ADMINISTRATION

·      *Review study medication injection procedures with patient

·      Assist with drug injection as necessary

·      BA058 80 µg or Placebo: collect used cartridges; supply new cartridges as
necessary

·      Teriparatide: collect used pens; supply new pre-filled pens as necessary

AFTER STUDY MEDICATION ADMINISTRATION

*Vital Signs - Repeat orthostatic blood pressure (60 minutes post-injection)

*ECGs - (60 minutes post-injection)

Blood Collection:  non-fasting

·      BA058 peak drug levels (at randomized time).  Only draw for patients
randomized to BA058, Placebo

·      Calcium (4 hours post-injection)

Bone Mineral Density

·      Perform hip (femoral neck), spine (L1-L4) and radius DXA

*Quantitative Bone Histomorphologic Assessment:

·      Discuss with patient and sign informed consent

·      Schedule visits to prepare for biopsy (between Visit 8 and Visit 9)

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

82

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

 

TREATMENT PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 9

 

End-of-Treatment Visit

 

 

Month 18

(± 7 days)

 

(one day after the last dose of study drug)

 

Physical Examination

*Recent Health Status

·      Document any changes from last visit

Patient Review

·      Review Calcium and Vitamin D supplement usage

·      Review study medication usage/injection site reactions

·      Review weekly patient diary

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

Calcium and Vitamin D Supplements

·      Assess and resupply patient’s Calcium and Vitamin D supplements

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

Local tolerance assessment

·      Investigator to review and assess injection sites

*Vital Signs and Weight

*Height (cm):  standing measurement with medical stadiometer

*ECG

Blood Collection:  fasting conditions (N.P.O. except water for 8 hours)

·      Chemistry

·      Hematology

·      Coagulation (PT and PTT)

·      PTH(1-84)

·      25-hydroxy Vitamin D levels

·      1, 25-dihydroxy Vitamin D levels

·      Serum markers of bone metabolism

·      PINP

·      bone-specific alkaline phosphatase

·      serum osteocalcin

·      serum CTX

·      BA058 trough drug levels (only for patients randomized to BA058, Placebo)

·      BA058 antibody levels

*24 Hour Urine Collection and Urinalysis

THERE IS NO STUDY MEDICATION ADMINISTRATION

·      Collect used study medication pens and cartridges

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 spine (L1-L4), hip, and wrist (in subset of patients) DXA.

Renal CT Scan

·      Perform renal CT scan on subset of patients who consented to this
procedure.

Discuss continuing treatment options with qualified patients

*Scheduling and Instructions for next Clinic Visit

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

83

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

 

FOLLOW-UP PERIOD

 

VISIT

 

STUDY DAY

 

ACTIVITIES

Visit 10

 

Final Study Visit

 

Month 19

(± 3 days)

 

*Recent Health Status

·      Document any changes from last visit

Calcium and Vitamin D Supplements

·      Collect any leftover supplements

*Vital Signs and Weight

*ECG

Discharge patient from study

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

·      Discuss continuing treatment options with qualified patients

 

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

*Refer to “Definitions of Common Procedures” for more detailed information
regarding these procedures

 

84

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

 

Body Mass Index Table

 

A BMI of 18.5 to 33, inclusive, is required for study participation.

 

 

 

Normal

 

Overweight

 

Obese

 

BMI

 

19

 

20

 

21

 

22

 

23

 

24

 

25

 

26

 

27

 

28

 

29

 

30

 

31

 

32

 

33

 

34

 

35

 

36

 

37

 

38

 

39

 

Height
(inches)

 

Body Weight (pounds)

 

58

 

91

 

96

 

100

 

105

 

110

 

115

 

119

 

124

 

129

 

134

 

138

 

143

 

148

 

153

 

158

 

162

 

167

 

172

 

177

 

181

 

186

 

59

 

94

 

99

 

104

 

109

 

114

 

119

 

124

 

128

 

133

 

138

 

143

 

148

 

153

 

158

 

163

 

168

 

173

 

178

 

183

 

188

 

193

 

60

 

97

 

102

 

107

 

112

 

118

 

123

 

128

 

133

 

138

 

143

 

148

 

153

 

158

 

163

 

168

 

174

 

179

 

184

 

189

 

194

 

199

 

61

 

100

 

106

 

111

 

116

 

122

 

127

 

132

 

137

 

143

 

148

 

153

 

158

 

164

 

169

 

174

 

180

 

185

 

190

 

195

 

201

 

206

 

62

 

104

 

109

 

115

 

120

 

126

 

131

 

136

 

142

 

147

 

153

 

158

 

164

 

169

 

175

 

180

 

186

 

191

 

196

 

202

 

207

 

213

 

63

 

107

 

113

 

118

 

124

 

130

 

135

 

141

 

146

 

152

 

158

 

163

 

169

 

175

 

180

 

186

 

191

 

197

 

203

 

208

 

214

 

220

 

64

 

110

 

116

 

122

 

128

 

134

 

140

 

145

 

151

 

157

 

163

 

169

 

174

 

180

 

186

 

192

 

197

 

204

 

209

 

215

 

221

 

227

 

65

 

114

 

120

 

126

 

132

 

138

 

144

 

150

 

156

 

162

 

168

 

174

 

180

 

186

 

192

 

198

 

204

 

210

 

216

 

222

 

228

 

234

 

66

 

118

 

124

 

130

 

136

 

142

 

148

 

155

 

161

 

167

 

173

 

179

 

186

 

192

 

198

 

204

 

210

 

216

 

223

 

229

 

235

 

241

 

67

 

121

 

127

 

134

 

140

 

146

 

153

 

159

 

166

 

172

 

178

 

185

 

191

 

198

 

204

 

211

 

217

 

223

 

230

 

236

 

242

 

249

 

68

 

125

 

131

 

138

 

144

 

151

 

158

 

164

 

171

 

177

 

184

 

190

 

197

 

203

 

210

 

216

 

223

 

230

 

236

 

243

 

249

 

256

 

69

 

128

 

135

 

142

 

149

 

155

 

162

 

169

 

176

 

182

 

189

 

196

 

203

 

209

 

216

 

223

 

230

 

236

 

243

 

250

 

257

 

263

 

70

 

132

 

139

 

146

 

153

 

160

 

167

 

174

 

181

 

188

 

195

 

202

 

209

 

216

 

222

 

229

 

236

 

243

 

250

 

257

 

264

 

271

 

71

 

136

 

143

 

150

 

157

 

165

 

172

 

179

 

186

 

193

 

200

 

208

 

215

 

222

 

229

 

236

 

243

 

250

 

257

 

265

 

272

 

279

 

72

 

140

 

147

 

154

 

162

 

169

 

177

 

184

 

191

 

199

 

206

 

213

 

221

 

228

 

235

 

242

 

250

 

258

 

265

 

272

 

279

 

287

 

73

 

144

 

151

 

159

 

166

 

174

 

182

 

189

 

197

 

204

 

212

 

219

 

227

 

235

 

242

 

250

 

257

 

265

 

272

 

280

 

288

 

295

 

74

 

148

 

155

 

163

 

171

 

179

 

186

 

194

 

202

 

210

 

218

 

225

 

233

 

241

 

249

 

256

 

264

 

272

 

280

 

287

 

295

 

303

 

75

 

152

 

160

 

168

 

176

 

184

 

192

 

200

 

208

 

216

 

224

 

232

 

240

 

248

 

256

 

264

 

272

 

279

 

287

 

295

 

303

 

311

 

76

 

156

 

164

 

172

 

180

 

189

 

197

 

205

 

213

 

221

 

230

 

238

 

246

 

254

 

263

 

271

 

279

 

287

 

295

 

304

 

312

 

320

 

 

 

 

Extreme Obesity

 

BMI

 

40

 

41

 

42

 

43

 

44

 

45

 

46

 

47

 

48

 

49

 

50

 

51

 

52

 

53

 

54

 

Height
(inches)

 

Body Weight (pounds)

 

58

 

191

 

196

 

201

 

205

 

210

 

215

 

220

 

224

 

229

 

234

 

239

 

244

 

248

 

253

 

258

 

59

 

198

 

203

 

208

 

212

 

217

 

222

 

227

 

232

 

237

 

242

 

247

 

252

 

257

 

262

 

267

 

60

 

204

 

209

 

215

 

220

 

225

 

230

 

235

 

240

 

245

 

250

 

255

 

261

 

266

 

271

 

276

 

61

 

211

 

217

 

222

 

227

 

232

 

238

 

243

 

248

 

254

 

259

 

264

 

269

 

275

 

280

 

285

 

62

 

218

 

224

 

229

 

235

 

240

 

246

 

251

 

256

 

262

 

267

 

273

 

278

 

284

 

289

 

295

 

63

 

225

 

231

 

237

 

242

 

248

 

254

 

259

 

265

 

270

 

278

 

282

 

287

 

293

 

299

 

304

 

64

 

232

 

238

 

244

 

250

 

256

 

262

 

267

 

273

 

279

 

285

 

291

 

296

 

302

 

308

 

314

 

65

 

240

 

246

 

252

 

258

 

264

 

270

 

276

 

282

 

288

 

294

 

300

 

306

 

312

 

318

 

324

 

66

 

247

 

253

 

260

 

266

 

272

 

278

 

284

 

291

 

297

 

303

 

309

 

315

 

322

 

328

 

334

 

67

 

255

 

261

 

268

 

274

 

280

 

287

 

293

 

299

 

306

 

312

 

319

 

325

 

331

 

338

 

344

 

68

 

262

 

269

 

276

 

282

 

289

 

295

 

302

 

308

 

315

 

322

 

328

 

335

 

341

 

348

 

354

 

69

 

270

 

277

 

284

 

291

 

297

 

304

 

311

 

318

 

324

 

331

 

338

 

345

 

351

 

358

 

365

 

70

 

278

 

285

 

292

 

299

 

306

 

313

 

320

 

327

 

334

 

341

 

348

 

355

 

362

 

369

 

376

 

71

 

286

 

293

 

301

 

308

 

315

 

322

 

329

 

338

 

343

 

351

 

358

 

365

 

372

 

379

 

386

 

72

 

294

 

302

 

309

 

316

 

324

 

331

 

338

 

346

 

353

 

361

 

368

 

375

 

383

 

390

 

397

 

73

 

302

 

310

 

318

 

325

 

333

 

340

 

348

 

355

 

363

 

371

 

378

 

386

 

393

 

401

 

408

 

74

 

311

 

319

 

326

 

334

 

342

 

350

 

358

 

365

 

373

 

381

 

389

 

396

 

404

 

412

 

420

 

75

 

319

 

327

 

335

 

343

 

351

 

359

 

367

 

375

 

383

 

391

 

399

 

407

 

415

 

423

 

431

 

76

 

328

 

336

 

344

 

353

 

361

 

369

 

377

 

385

 

394

 

402

 

410

 

418

 

426

 

435

 

443

 

 

Source: Adapted from Clinical Guidelines on the identification, Evaluation, and
Treatment of Overweight and Obesity in Adults: The Evidence Report.

 

85

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

 

WHO (World Health Organization) Toxicity Criteria by Grade

 

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

 

 

86

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

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

 

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

 

 

87

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

 

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

 

—

 

—

 

 

88

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

 

Category
Toxicity (units)

 

Grade 0

 

Grade 1

 

Grade 2

 

Grade 3

 

Grade 4

 

Allergy

 

 

 

 

 

 

 

 

 

 

 

Allergy

 

none

 

transient rash, drug fever <38°C (<100.4°F)

 

urticaria, drug fever 38°C (100.4°F), 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 - 38.0° C
98.7° - 100.4° F

 

38.1 - 40.0° C
100.5 - 104° F

 

> 40.0°C (> 104° F) for less than 24hrs

 

> 40.0° C (> 104° 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

 

 

 

 

 

 

 

 

 

 

89

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

 

Declaration of Helsinki

 

WORLD MEDICAL ASSOCIATION DECLARATION OF HELSINKI
Ethical Principles for Medical Research Involving Human Subjects
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and
amended by the:
29th WMA General Assembly, Tokyo, Japan, October 1975
35th WMA General Assembly, Venice, Italy, October 1983
41st WMA General Assembly, Hong Kong, September 1989
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996
52nd WMA General Assembly, Edinburgh, Scotland, October 2000
53rd WMA General Assembly, Washington 2002 (Note of Clarification on paragraph
29 added)
55th WMA General Assembly, Tokyo 2004 (Note of Clarification on Paragraph 30
added)
59th WMA General Assembly, Seoul, October 2008

 

A. INTRODUCTION

 

1. The World Medical Association (WMA) has developed the Declaration of Helsinki
as a statement of ethical principles for medical research involving human
subjects, including research on identifiable human material and data.

 

The Declaration is intended to be read as a whole and each of its constituent
paragraphs should not be applied without consideration of all other relevant
paragraphs.

 

2. Although the Declaration is addressed primarily to physicians, the WMA
encourages other participants in medical research involving human subjects to
adopt these principles.

 

3. It is the duty of the physician to promote and safeguard the health of
patients, including those who are involved in medical research. The physician’s
knowledge and conscience are dedicated to the fulfilment of this duty.

 

4. The Declaration of Geneva of the WMA binds the physician with the words, “The
health of my patient will be my first consideration,” and the International Code
of Medical Ethics declares that, “A physician shall act in the patient’s best
interest when providing medical care.”

 

5. Medical progress is based on research that ultimately must include studies
involving human subjects. Populations that are underrepresented in medical
research should be provided appropriate access to participation in research.

 

6. In medical research involving human subjects, the well-being of the
individual research subject must take precedence over all other interests.

 

7. The primary purpose of medical research involving human subjects is to
understand the causes, development and effects of diseases and improve
preventive, diagnostic and therapeutic interventions (methods, procedures and
treatments). Even the best current interventions must be evaluated continually
through research for their safety, effectiveness, efficiency, accessibility and
quality.

 

8. In medical practice and in medical research, most interventions involve risks
and burdens.

 

9. Medical research is subject to ethical standards that promote respect for all
human subjects and protect their health and rights. Some research populations
are particularly vulnerable and need special protection. These include those who
cannot give or refuse consent for themselves and those who may be vulnerable to
coercion or undue influence.

 

10. Physicians should consider the ethical, legal and regulatory norms and
standards for research involving human subjects in their own countries as well
as applicable international norms and standards. No national or international
ethical, legal or regulatory requirement should reduce or eliminate any of the
protections for research subjects set forth in this Declaration.

 

B. PRINCIPLES FOR ALL MEDICAL RESEARCH

 

11. It is the duty of physicians who participate in medical research to protect
the life, health, dignity, integrity, right to self-determination, privacy, and
confidentiality of personal information of research subjects.

 

12. Medical research involving human subjects must conform to generally accepted
scientific principles, be based on a thorough knowledge of the scientific
literature, other relevant sources of information, and adequate laboratory and,
as appropriate, animal experimentation. The welfare of animals used for research
must be respected.

 

90

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

 

13. Appropriate caution must be exercised in the conduct of medical research
that may harm the environment.

 

14. The design and performance of each research study involving human subjects
must be clearly described in a research protocol. The protocol should contain a
statement of the ethical considerations involved and should indicate how the
principles in this Declaration have been addressed. The protocol should include
information regarding funding, sponsors, institutional affiliations, other
potential conflicts of interest, incentives for subjects and provisions for
treating and/or compensating subjects who are harmed as a consequence of
participation in the research study. The protocol should describe arrangements
for post-study access by study subjects to interventions identified as
beneficial in the study or access to other appropriate care or benefits.

 

15. The research protocol must be submitted for consideration, comment, guidance
and approval to a research ethics committee before the study begins. This
committee must be independent of the researcher, the sponsor and any other undue
influence. It must take into consideration the laws and regulations of the
country or countries in which the research is to be performed as well as
applicable international norms and standards but these must not be allowed to
reduce or eliminate any of the protections for research subjects set forth in
this Declaration. The committee must have the right to monitor ongoing studies.
The researcher must provide monitoring information to the committee, especially
information about any serious adverse events. No change to the protocol may be
made without consideration and approval by the committee.

 

16. Medical research involving human subjects must be conducted only by
individuals with the appropriate scientific training and qualifications.
Research on patients or healthy volunteers requires the supervision of a
competent and appropriately qualified physician or other health care
professional. The responsibility for the protection of research subjects must
always rest with the physician or other health care professional and never the
research subjects, even though they have given consent.

 

17. Medical research involving a disadvantaged or vulnerable population or
community is only justified if the research is responsive to the health needs
and priorities of this population or community and if there is a reasonable
likelihood that this population or community stands to benefit from the results
of the research.

 

18. Every medical research study involving human subjects must be preceded by
careful assessment of predictable risks and burdens to the individuals and
communities involved in the research in comparison with foreseeable benefits to
them and to other individuals or communities affected by the condition under
investigation.

 

19. Every clinical trial must be registered in a publicly accessible database
before recruitment of the first subject.

 

20. Physicians may not participate in a research study involving human subjects
unless they are confident that the risks involved have been adequately assessed
and can be satisfactorily managed. Physicians must immediately stop a study when
the risks are found to outweigh the potential benefits or when there is
conclusive proof of positive and beneficial results.

 

21. Medical research involving human subjects may only be conducted if the
importance of the objective outweighs the inherent risks and burdens to the
research subjects.

 

22. Participation by competent individuals as subjects in medical research must
be voluntary. Although it may be appropriate to consult family members or
community leaders, no competent individual may be enrolled in a research study
unless he or she freely agrees.

 

23. Every precaution must be taken to protect the privacy of research subjects
and the confidentiality of their personal information and to minimize the impact
of the study on their physical, mental and social integrity.

 

24. In medical research involving competent human subjects, each potential
subject must be adequately informed of the aims, methods, sources of funding,
any possible conflicts of interest, institutional affiliations of the
researcher, the anticipated benefits and potential risks of the study and the
discomfort it may entail, and any other relevant aspects of the study. The
potential subject must be informed of the right to refuse to participate in the
study or to withdraw consent to participate at any time without reprisal.
Special attention should be given to the specific information needs of
individual potential subjects as well as to the methods used to deliver the
information. After ensuring that the potential subject has understood the
information, the physician or another appropriately qualified individual must
then seek the potential subject’s freely-given informed consent, preferably in
writing. If the consent cannot be expressed in writing, the non-written consent
must be formally documented and witnessed.

 

25. For medical research using identifiable human material or data, physicians
must normally seek consent for the collection, analysis, storage and/or reuse.
There may be situations where consent would be impossible or impractical to
obtain for such research or would pose a threat to the validity of the research.
In such situations the research may be done only after consideration and
approval of a research ethics committee.

 

91

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

 

26. When seeking informed consent for participation in a research study the
physician should be particularly cautious if the potential subject is in a
dependent relationship with the physician or may consent under duress. In such
situations the informed consent should be sought by an appropriately qualified
individual who is completely independent of this relationship.

 

27. For a potential research subject who is incompetent, the physician must seek
informed consent from the legally authorized representative. These individuals
must not be included in a research study that has no likelihood of benefit for
them unless it is intended to promote the health of the population represented
by the potential subject, the research cannot instead be performed with
competent persons, and the research entails only minimal risk and minimal
burden.

 

28. When a potential research subject who is deemed incompetent is able to give
assent to decisions about participation in research, the physician must seek
that assent in addition to the consent of the legally authorized representative.
The potential subject’s dissent should be respected.

 

29. Research involving subjects who are physically or mentally incapable of
giving consent, for example, unconscious patients, may be done only if the
physical or mental condition that prevents giving informed consent is a
necessary characteristic of the research population. In such circumstances the
physician should seek informed consent from the legally authorized
representative. If no such representative is available and if the research
cannot be delayed, the study may proceed without informed consent provided that
the specific reasons for involving subjects with a condition that renders them
unable to give informed consent have been stated in the research protocol and
the study has been approved by a research ethics committee. Consent to remain in
the research should be obtained as soon as possible from the subject or a
legally authorized representative.

 

30. Authors, editors and publishers all have ethical obligations with regard to
the publication of the results of research. Authors have a duty to make publicly
available the results of their research on human subjects and are accountable
for the completeness and accuracy of their reports. They should adhere to
accepted guidelines for ethical reporting. Negative and inconclusive as well as
positive results should be published or otherwise made publicly available.
Sources of funding, institutional affiliations and conflicts of interest should
be declared in the publication. Reports of research not in accordance with the
principles of this Declaration should not be accepted for publication.

 

C. ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH MEDICAL CARE

 

31. The physician may combine medical research with medical care only to the
extent that the research is justified by its potential preventive, diagnostic or
therapeutic value and if the physician has good reason to believe that
participation in the research study will not adversely affect the health of the
patients who serve as research subjects.

 

32. The benefits, risks, burdens and effectiveness of a new intervention must be
tested against those of the best current proven intervention, except in the
following circumstances:

 

· The use of placebo, or no treatment, is acceptable in studies where no current
proven intervention exists; or

 

· Where for compelling and scientifically sound methodological reasons the use
of placebo is necessary to determine the efficacy or safety of an intervention
and the patients who receive placebo or no treatment will not be subject to any
risk of serious or irreversible harm. Extreme care must be taken to avoid abuse
of this option.

 

33. At the conclusion of the study, patients entered into the study are entitled
to be informed about the outcome of the study and to share any benefits that
result from it, for example, access to interventions identified as beneficial in
the study or to other appropriate care or benefits.

 

34. The physician must fully inform the patient which aspects of the care are
related to the research. The refusal of a patient to participate in a study or
the patient’s decision to withdraw from the study must never interfere with the
patient-physician relationship.

 

35. In the treatment of a patient, where proven interventions do not exist or
have been ineffective, the physician, after seeking expert advice, with informed
consent from the patient or a legally authorized representative, may use an
unproven intervention if in the physician’s judgement it offers hope of saving
life, re-establishing health or alleviating suffering. Where possible, this
intervention should be made the object of research, designed to evaluate its
safety and efficacy. In all cases, new information should be recorded and, where
appropriate, made publicly available.

 

92

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

 

Work Statement NB-1

Attachment F

Reports and Information Management/Regular Meetings

 

The Project Committee for Work Statement NB-1 shall be composed of the following
members from Radius and the following members from NB:

 

Radius Members:  (1) Nicholas Harvey, (2) Louis O’Ded and (3) Richard Lyttle.

 

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

 

Attachment 2, Attachment F-2

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

 

Work Statement NB-1

Attachment G

Special Insurance

 

Radius will maintain the following insurance with respect to the following
jurisdictions during the conduct of the clinical study that is the subject of
Work Statement NB-1:

 

Brazil

Insurer, coverage:  QBE Brasil Seguros S.A, $1,000,000

Czech Republic

Insurer, coverage:  Lloyd’s of London € 2,500,000, € 250,000 (per subject)

Denmark

Insurer, coverage:  Lloyd’s of London, € 500,000,000

Estonia

Insurer, coverage:  Lloyd’s of London € 500,000,000

Hong Kong

Insurer, coverage:  HDI — Gerling, 20,000,000 HKD, 10,000,000 HKD (per subject)

Lithuania

Insurer, coverage:  Lloyd’s of London, 24,000,000 LTL, 100,000 LTL (per subject)

Poland

Insurer, coverage:  Lloyd’s of London, € 500,000,000

Romania

Insurer, coverage:  Lloyd’s of London, € 500,000,000

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 2, Attachment G-1

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

 

Work Statement NB-1

Attachment H

Transfer of Obligation

 

See Work Statement NB-1 Attachment C.

 

Attachment 2, Attachment H-1

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

 

Attachment 3

Form of Enterprise CTA

CLINICAL TRIAL AGREEMENT

 

Protocol No. BA058-05-003

 

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:

 

Protocol No. BA058-05-003, “A Randomized, Double-blind, Placebo-controlled,
Comparative Phase 3 Multicenter Study to Evaluate the Safety and Efficacy of
BA058 (“Study Drug”) for Injection for Prevention of Fracture in Ambulatory
Postmenopausal Women with Severe Osteoporosis and at Risk of Fracture” (together
with any of its subsequent amendments, the “Protocol”), 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-Czech, Masarykovo náměstí 2667, 530 02
Pardubice, Czech Republic

 

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

 

10.                   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

 

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.

 

Attachment 3-1

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

 

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
thousand four hundred (2,400) 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.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 3-2

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

 

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.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 3-3

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

 

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 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.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 3-4

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

 

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.

 

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:

 

Attachment 3-5

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

 

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

 

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.

 

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

* Confidential Treatment Requested by the Registrant. Redacted Portion Filed
Separately with the Commission.

 

Attachment 3-6

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

 

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.

 

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.

 

NORDIC BIOSCIENCE A/S

Bente Riis, Head, Clinical Development

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

Ralph Reyes, CEO

 

 

 

 

Signature

 

 

 

 

 

Signature

 

 

Attachment 3-7

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

 

Date:

 

 

 

 

 

 

Date:

 

 

Attachment 3-8

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

 

SCHEDULE A

 

Cost and Payment:

 

Attachment 3-9

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

 

EXHIBIT A

 

PRINCIPAL INVESTIGATOR’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. BA058-05-003:

 

“A Randomized, Double-blind, Placebo-controlled, Comparative Phase 3 Multicenter
Study to Evaluate the Safety and Efficacy of BA058 for Injection for Prevention
of Fracture in Ambulatory Postmenopausal Women with Severe Osteoporosis and at
Risk of Fracture”

 

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:

 

 

 

Attachment 3-10

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

 

Exhibit B

Form of Indemnity Letter

 

[RADIUS HEALTH, INC. LETTERHEAD]

 

[Name of Clinical Study Site]

[Address]

[City, State, Country]

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

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

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

CCBR-Tallinn, Pärna 4, 10128 Tallinn, Estonia

CCBR-Vilnius, Smélio 20, Vilnius, Lithuania

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

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

[CCBR-Czech, Hybešova 18, 60200 Brno, Czech Republic]

CCBR-Czech, Masarykovo náměstí 2667, 530 02 Pardubice, Czech Republic

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

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

 

Re:  Clinical Trial No. BA058-05-003 (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                  , 2010 among Center for Clinical and
Basic Research A/Sk (“CCBR”) on behalf of itself and its affiliates
CCBR-Ballerup, CCBR-Ålborg, CCBR-Vejle, CCBR-Tallinn, CCBR-Vilnius,
CCBR-Bucharest, CCBR-Rio de Janeiro, CCBR-Czech, Hybešova CCBR-Czech Masarykovo,
CCBR-Warsaw 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. BA058-05-003, “A Randomized, Double-blind,
Placebo-controlled, Comparative Phase 3 Multicenter Study to Evaluate the Safety
and Efficacy of BA058 (“Study Drug”) for Injection for Prevention of Fracture in
Ambulatory Postmenopausal Women with Severe Osteoporosis and at Risk of
Fracture” (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 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

 

 

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

 

Attachment 4

Form of Indemnity Letter

 

[RADIUS HEALTH, INC. LETTERHEAD]

 

[Name of Clinical Study Site]

[Address]

[City, State, Country]

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

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

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

CCBR-Tallinn, Pärna 4, 10128 Tallinn, Estonia

CCBR-Vilnius, Smélio 20, Vilnius, Lithuania

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

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

[CCBR-Czech, Hybešova 18, 60200 Brno, Czech Republic]

CCBR-Czech, Masarykovo náměstí 2667, 530 02 Pardubice, Czech Republic

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

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

 

Re:  Clinical Trial No. BA058-05-003 (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                  , 2010 among Center for Clinical and
Basic Research A/Sk (“CCBR”) on behalf of itself and its affiliates
CCBR-Ballerup, CCBR-Ålborg, CCBR-Vejle, CCBR-Tallinn, CCBR-Vilnius,
CCBR-Bucharest, CCBR-Rio de Janeiro, CCBR-Czech, Hybešova CCBR-Czech Masarykovo,
CCBR-Warsaw 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. BA058-05-003, “A Randomized, Double-blind,
Placebo-controlled, Comparative Phase 3 Multicenter Study to Evaluate the Safety
and Efficacy of BA058 (“Study Drug”) for Injection for Prevention of Fracture in
Ambulatory Postmenopausal Women with Severe Osteoporosis and at Risk of
Fracture” (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 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

 

Attachment 4-1

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

 

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

 

 

Attachment 4-2

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

 

Confidential Treatment Requested

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

 

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

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement (“Work Statement NB-1”) as of March 29, 2011
(“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-1 (“Amendment No. 1”)
effective as of December 9, 2011 (“Amendment Date”). Capitalized terms used in
this Amendment No. 1 and not defined herein are used with the meanings ascribed
to them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 1, the parties agree as follows:

 

1.  Addition of non-CCBR A/S Sites in India and the United States of
America.  (a)  Radius or its authorized representative will contract with
certain clinical trial sites in India and the United States of America to enroll
patients in the clinical study that is the subject of Work Statement NB-1 in
order to facilitate the timely achievement of the enrollment targets for such
study.

 

(b)  The NB representations and warranties set forth in Sections 8.2, 8.3, 8.5
and 8.6(ii) of the Agreement shall not apply to the personnel, including
Clinical Investigators, that perform the clinical study at the study sites
located in India or the United States.  Radius shall be responsible for securing
the applicable representations and warranties from these clinical study sites
and personnel, including Clinical Investigators.

 

(c)  The Study Assumptions table on the first page of Attachment A to Work
Statement NB-1 (Attachment 2 to the Agreement) is amended to increase the total
Number of Sites from 11 to 35-37, to add the following information concerning
sites in India and the United States of America as well as additional sites in
Argentina and Peru, to increase the number of sites in Poland and the Czech
Republic, to increase the number of patients to be pre-screened to reflect
patient recruitment experience to date, to add a 2-month screening period and to
add an additional patient visit at month 15.  As amended, the Study Assumptions
table will read in full as follows:

 

Protocol Number

 

BA058-05-003

Number of Sites:

 

35-37

Denmark

 

3

Estonia

 

1

Lithuania

 

1

Romania

 

1

Poland

 

2

Czech Republic

 

3

Brazil

 

1-2

Argentina

 

1-2

Peru

 

1

Hong Kong

 

1

India

 

15

USA

 

5

Number of Patients to be Pre-Screened

 

[*]

Number of Patients to Enroll:

 

2,400

Screening Period:

 

2 months

Treatment Period:

 

18 months

Safety Follow up Period

 

1 month

Visits per Completed Subject:

 

11

 

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

[*] 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

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

 

(d)  The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new Paragraph
(10) immediately following Paragraph (9) of the Payment Schedule, which shall
read in full as follows:

 

“(10)  The purchase price for the Services with respect to subjects enrolled at
the study sites located in India or the United States of America shall be paid
solely in cash and shall not include payment of a First Monthly Amount detailed
under Paragraph (4).  The purchase price for the Services with respect to
subjects enrolled at the study sites located in India or the United States of
America shall include payment of a separate amount in consideration of the
incremental administrative costs that NB will bear to integrate and manage data
being supplied by these clinical sites.  The amount of this incremental payment
shall be:

 

(a)  €717,700 for the EURO denominated portion of the clinical study that is the
subject of Work Statement NB-1 for the 15 study sites located in India and
$289,663 for the U.S. Dollar denominated portion of the clinical study that is
the subject of Work Statement NB-1 for the 15 study sites located in India
(exclusive of certain shipping costs concerning central imaging services which
shall be billed separately).

 

(b)  €1,234,790 for the EURO denominated portion of the clinical study that is
the subject of Work Statement NB-1 for the 5 study sites located in the United
States of America and $143,369 for the U.S. Dollar denominated portion of the
clinical study that is the subject of Work Statement NB-1 for the 5 study sites
located in the United States of America.

 

Radius shall be invoiced and shall pay NB the U.S. Dollar denominated portion of
these incremental fees ($[*] for the 15 study sites located in India and $[*]
for the 5 study sites located in the United States of America) as pass thru
costs.  Radius shall be invoiced and shall pay NB €[*] of the EURO denominated
portion of these incremental fees (relating to the expansion of the eCRF to the
20 new sites in India and the United States of America) as pass through costs.

 

Radius shall pay NB €[*] of the EURO denominated portion of these incremental
fees for the 15 study sites located in India and €[*] of the EURO denominated
portion of these incremental fees for the 5 study sites located in the United
States of America within 15 days of the Effective Date.  Radius shall pay NB the
balance of the EURO denominated portion of these incremental fees (€[*] for the
15 study sites located in India; and €[*] for the 5 study sites located in the
United States of America) in pro rata installments at the time it pays each
installment of the Second Monthly Amount and the Third Monthly Amount.”

 

(e)  The “Trial Activities and Delegation of Responsibilities” table set forth
in Attachment C to Work Statement NB-1 (Attachment 2 to the Agreement) is
amended to provide that NB, as Service provider, shall not have the
responsibilities assigned to it under the following activity categories listed
in Attachment C with respect to the clinical study sites located in India and
the United States of America.  NB shall continue to hold all other
responsibilities enumerated as those of the “Service provider” in Attachment C
with respect to the clinical study sites located in India and the United States
of America.  The specific Service provider responsibilities that NB is relieved
of with respect to the study sites located in India and the United States of
America are as follows having reference to the activity categories listed in
Attachment C:

 

Regulatory

 

(i) IND/CTA Preparation, (ii) CTA Submissions & Updates, (iii) Informed Consent
Form (ICF, PIS), (iv) Ethics Committees/IRB Submissions & Updates, (v) Health
Authority SAE Submissions & Follow Up(s), (vi) Legal Representative and
Regulatory & Study Documents translations and (vii) Regulatory & Study Documents
translations.

 

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

[*] 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

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

 

Clinical Trial Materials

 

(i) Vitamin D & Calcium, (ii) Tote Bags/Ice Packs (Sponsor will be responsible
for these in all jurisdictions) and (iii) Study Drug Reconciliation — Patient,
Site, & Study.

 

Clinical Trial Conduct

 

(i) Clinical Trial Project Plan (Sponsor will be responsible to provide
India-specific information) (ii) Clinical Trial Budget Forecasting & Tracking,
(iii) Vendor Management — Labs, X-ray, Dexa, Renal, Imaging, ECG, (iv) Vendor
Management - PK, Antibody, Drug Manufacture/Package, IVRS, Central IRB (Sponsor
will now be responsible for the Central IRB for all jurisdictions), (v) Patient
Recruitment, Screening, Enrollment (for India but Service provider shall remain
responsible for USA), (vi) Site Selection, (vii) Site Management (for India but
Service provider will be responsible for USA), (vii) Site Confidentiality
Agreements, (viii) Site Contract/Agreement, (ix) Clinical Trial Monitoring &
Plan (for India but Service provider will be responsible for USA), (x) Clinical
Trial Monitoring Reports (for India but Service provider shall remain
responsible for USA), (xi) Clinical Trial Monitors (for India but Service
provider will be responsible for USA), (xii) Monitor Travel Expense (for India
but Service provider will be responsible for USA), (xiii) CRA Meetings (for
India but Service provider will be responsible for USA) (xiv) Trial Staff
Training (for India but Service provider will be responsible for USA),
(xv) Trial Master File and Site Trial File (for India but Service provider will
be responsible for USA), (xvi) Investigator Site Payments, (xvii) Essential
Document Collection (for India but Service provider will be responsible for USA)
and (xviii) Printing Study Documents (for India but Service provider will be
responsible for USA).

 

Labs

 

(i)Central or Local Safety Labs, (ii) Central/Safety/Bone Marker Labs Data
Reporting (SI Units), (iii) Central/Safety/Bone Marker Labs Data Reporting (SI
Units), (iv) Lab Specimen Management, Shipping & Reconciliation, (v) Lab Kits &
Supplies,  (vi) Lab Sample Storage, (vii)Lab Sample Destruction.

 

Safety & Pharmacovigilance

 

(i) Annual & Periodic Drug Safety Update Generation & Filing (ii) Health
Authority reporting and (iii) Final Safety Report for HA, EC, IRB submission. 
In addition, Service provider shall no longer be responsible for Annual &
Periodic Drug Safety Update Generation & Filing for European Union countries, in
these countries, Sponsor shall be responsible for this activity and Service
provider’s responsibility shall be limited to providing Sponsor with data from
the studies in such countries that are being managed by Service provider.

 

Quality

 

Health Authority inspections/audits (for India but Service provider will be
responsible for USA).

 

(f)  Attachment G to Work Statement NB-1 (Attachment 2 to the Agreement) is
amended to provide that Radius will maintain the following insurance with
respect to the following additional jurisdictions during the conduct of the
clinical study that is the subject of Work Statement NB-1:

 

“India

Insurer, coverage: ICICI Lombard, $[*] (Coverage quoted, not yet bound).

 

United States of America

Insurer, coverage:  Chubb, $[*].

 

Argentina

Insurer, coverage: SMG Seguros, $[*].

 

Peru

Insurer, coverage: La Positiva, $[*].”

 

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-1 are hereby ratified and confirmed and shall remain in full force
and effect.  The term “Work Statement NB-1”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-1 as amended by this
Amendment No. 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.

 

3

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

 

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.

 

[remainder of this page intentionally left blank - signature page follows]

 

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

[*] 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.

 

4

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

 

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/ Michael S. Wyzga

 

/s/ Bente Juel Riis

By: Michael S. Wyzga

 

By: Bente Juel Riis

Title: President and Chief Executive Officer

 

Title: Medical Director

 

 

 

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

 

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

[*] 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.

 

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

 

[g17732la51i001.gif]

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 2 TO WORK STATEMENT NB-1

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1 to Work Statement NB-1 as of December 9, 2011
(as amended, “Work Statement NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 2 to Work Statement NB-1 (“Amendment No. 2”)
effective as of June 18, 2012 (“Amendment Date”). Capitalized terms used in this
Amendment No. 2 and not defined herein are used with the meanings ascribed to
them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 2, the parties agree as follows:

 

1. Addition of Sites and Adjustment to Payment Schedule (a)  At Radius’ request,
NB will contract with up to 12 CCBR and non-CCBR A/S Sites in Europe, Brazil and
Argentina to be managed by NB (“New Sites”) to enroll patients in the clinical
study that is the subject of Work Statement NB-1 in order to facilitate the
timely achievement of the enrollment targets for such study.  Radius wishes to
provide for payment to NB for Services for the New Sites.  In addition, Radius
and NB also wish to provide for additional payments to NB for certain extra site
activities as well as provide for adjustments in payments to NB related to
subjects to be enrolled in clinical trial sites in India and the United States
of America.

 

(b)  The NB representations and warranties set forth in Sections 8.2, 8.3, 8.5
and 8.6(ii) of the Agreement shall apply to the personnel, including Clinical
Investigators, that perform the clinical study at the New Sites.  NB shall be
responsible for securing the applicable representations and warranties from
these clinical study sites and personnel, including Clinical Investigators.

 

(c)  The Study Assumptions table on the first page of Attachment A to Work
Statement NB-1 (Attachment 2 to the Agreement) is amended to increase the total
Number of Sites from 35-37 to 42. As amended, the Study Assumptions table will
read in full as follows:

 

Protocol Number

 

BA058-05-003

 

Number of Sites:

 

42

 

Denmark

 

3

 

Estonia

 

2

 

Lithuania

 

1

 

Romania

 

1

 

Poland

 

6

 

Czech Republic

 

3

 

Brazil

 

4

 

Argentina

 

2

 

Hong Kong

 

1

 

India

 

15

 

USA

 

4

 

Number of Patients to be Pre-Screened

 

[*]

 

Number of Patients to Enroll:

 

2,400

 

Screening Period:

 

2 months

 

Treatment Period:

 

18 months

 

Safety Follow up Period

 

1 month

 

Visits per Completed Subject:

 

11

 

 

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

[*] 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.

 

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

 

[g17732la51i001.gif]

 

(d) The paragraph at the bottom Attachment B to Work Statement NB-1 (Budgets,
Fees, Pass-through Costs, and Payment Schedule*) is hereby amended to read in
full as follows:

 

“*The pricing specified in this Budget is calculated based upon 2,040 subjects
randomized and completed at sites managed by NB, excluding sites in India and
the United State of America, and is not subject to any adjustment for the number
of patients to be Pre-screened/Advertisement, the screen failure rate after the
Patient Informed Consent has been signed, or the drop-out rate. However, this
Budget as well as the Bonus Equity Payment Amount under the Amended and Restated
Stock Issuance Agreement dated May 16, 2011 shall each be reduced by an amount
of €[*] per subject for any subjects enrolled in India or the United States.
Such reduction to be applied in pro rata installments at the time of payment of
the Second Monthly Amount and the Third Monthly Amount. Otherwise, all pricing
will be adjusted on a pro rata fashion to reflect the actual study activities
completed by the study subjects.  For bone biopsies, this pro rata adjustment
for biopsies less than or greater than 200 shall be €[*] for each bone biopsy at
sites managed by NB and €[*] for sites in India and the United State of America.
For CT-scans, this pro rata adjustment for CT-scans less than or greater than
300 shall be €[*] for each CT-scan at sites managed by NB.”

 

(e) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new sixth subparagraph to
the end of Paragraph (10) of the Payment Schedule, which shall appear
immediately following the fifth paragraph and shall read in full as follows:

 

“The pricing specified for the Services with respect to subjects enrolled at the
study sites located in India or the United States of America is based upon 300
subjects randomized at 15 sites in India and 75 subjects randomized at 5 sites
in the United States of America and shall be adjusted on a pro rata basis to
reflect the actual number of sites initiated and the actual number of subjects
enrolled in India and the United States of America. Such adjustment to be
applied in pro rata installments at the time of payment of the Second Monthly
Amount and the Third Monthly Amount.”

 

(f) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new Paragraph (11)
immediately following Paragraph (10) of the Payment Schedule, which shall read
in full as follows:

 

“(11)  The purchase price for the Services with respect to the extra site
activities (at currently existing sites) as well as for the addition of the New
Sites managed by NB located in Europe, Brazil and Argentina shall be paid solely
in cash and shall include payment of a First Monthly Amount detailed under
Paragraph (4). The amount of this incremental payment for the Services shall be:

 

(a)  €811,200 for the extra site activities (at currently existing sites) based
upon 2,400 subject randomized at clinical sites managed by NB and shall be
reduced on a pro rata basis for any patients enrolled in India or the United
States.

 

(b) €100,000 for the extra site activities associated with obtaining new
informed consent from subjects already enrolled in the Phase 3 study due to
Protocol amendments.

 

(c) €2,739,450 for the EURO denominated portion and $205,540 for the U.S. Dollar
denominated portion for the 12 New Sites study sites located in Europe, Brazil
and Argentina. Radius shall be invoiced and shall pay the EURO denominated
portion of any shipmen costs related to Synarc Research Laboratory as pass
through costs.

 

Radius shall pay NB €[*] of the EURO denominated portion and $[*] for the U.S.
Dollar denominated portion of these incremental fees for the extra site
activities and the New Sites located in Europe, Brazil and Argentina within 15
days of the Effective Date.  Radius shall pay NB the balance of the EURO and
U.S. Dollar incremental fees (€[*] and $[*]) in pro rata installments at the
time it pays each installment of the Second Monthly Amount and the Third Monthly
Amount.”

 

(g)  The “Trial Activities and Delegation of Responsibilities” table set forth
in Attachment C to Work Statement NB-1 (Attachment 2 to the Agreement), as
amended, shall apply to New Sites managed by NB.

 

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

[*] 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

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[g17732la51i001.gif]

 

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

 

3.  General.  This Amendment No. 2 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument

 

[remainder of this page intentionally left blank - signature page follows]

 

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

[*] 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.

 

3

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

 

[g17732la51i001.gif]

 

IN WITNESS WHEREOF the parties have caused this Amendment No.2 to be executed by
their respective duly authorized officers, and have duly delivered and executed
this Amendment No. 2 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

 

 

 

 

/s/ B. Nicholas Harvey

 

/s/ Bente Juel Riis

By: B. N. Harvey

 

By: Bente Juel Riis

Title: CFO

 

Title: Medical Director

 

 

 

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

 

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

[*] 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.

 

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

 

Execution Copy

 

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

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1 and Amendment No. 2 to Work Statement NB-1 as of
December 9, 2011and June 18, 2012 respectively, (as amended, “Work Statement
NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 3 to Work Statement NB-1 (“Amendment No. 3”)
effective as of November 6, 2013 (“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-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 3, the parties agree as follows:

 

1. Addition of Antibody Surveillance Program (a) At Radius’ request, NB will
initiate an antibody surveillance program at CCBR and non-CCBR sites to monitor
any patients with positive antibodies in the clinical study that is the subject
of Work Statement NB-1 (collectively, “Ab Services”). Radius wishes to provide
for payment to NB for these Ab Services under Work Statement NB-1.

 

(b)  The NB representations and warranties set forth in Sections 8.2, 8.3, 8.5
and 8.6(ii) of the Agreement shall apply to the personnel, including Clinical
Investigators, that perform the Ab Services.  NB shall be responsible for
securing the applicable representations and warranties from these clinical study
sites and personnel, including Clinical Investigators.

 

(c) A new section at the bottom Attachment B to Work Statement NB-1 (Budgets,
Fees, Pass-through Costs, and Payment Schedule*) is hereby amended to read in
full as follows:

 

“Antibody — BA058-05-003

 

Cost Proposal 08 October 2013

 

Sponsor:

 

RADIUS

 

 

Protocol ID:

 

Antibody - BA058-05-003

 

 

Development Phase:

 

N/A

 

 

Disease:

 

Osteoporosis

 

 

Nordic Start Study Activity

 

1-Jun-13

 

 

Expected Date of first follow up patient first visit

 

24-Apr-13

 

Based on FPLT 24-OCT-2012

Expected Date of last follow up patient first visit

 

1-Apr-15

 

Based on LPLV 01-OCT-2014

Expected Date of last follow up patient last visit

 

1-Oct-15

 

Based on Last FUP last visit 6 months after Last FUP first vist

Expected Length of total Follow-up period (months):

 

30

 

 

Duration of Nordic Involvement

 

16

 

Period from 01-JUN-13 to 31-JUN-14 is covered in the antibody budget for 007.

Number of visits per patient:

 

2

 

Estimated 2 extra samples per positive patient up to a period of 12 months after
last study drug.

Number of Countries:

 

10

 

 

Number of Sites:

 

28

 

 

 

 

1

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

 

Total Budget 

 

EURO

 

 

Clinic Fee

 

€40 per scheduled visit; €96 per unscheduled visit

 

Estimated 75% unscheduled visits

CRO Activities (Nordic Bioscience)

 

32,640

 

Period until LPLV in 005 is partly covered in existing work orders. Only extra
is increased study and site management and pharmacovigilance

Central Lab Fee (Synarc Lab)

 

€26.40 per sample per patient

 

Shipment not included. Shipment to be invoiced as pass through. Estimated to be
180,000 Euro

EDC system

 

0

 

Not applicable

 

Pass through Cost

 

EURO

 

 

Translation

 

Not included

 

 

Investigator Meeting

 

Not included

 

 

Lab shipments

 

Not included

 

 

Submission to EC 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

 

 

 

The CRO fee is not subject to any adjustment for the number of antibody positive
patients. The Clinic Fee and Central Lab Fee will be adjusted to reflect the
actual number of antibody positive patients and visits completed for
surveillance activities. The Central Lab Fee will be adjusted on a pro rata
basis based on the number of samples per antibody positive patient.

 

(d) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new Paragraph (12)
immediately following Paragraph (11) of the Payment Schedule, which shall read
in full as follows:

 

“(12)  The purchase price for the Ab Services shall be paid solely in cash as
follows:

 

(a)  The CRO fee shall be paid in fixed monthly installments over the expected
30 month period of delivery of the Ab Services commencing May 1, 2013 with an
expected last patient, last follow-up visit of October 1, 2015 equal to €1,088
per month.

 

(b) The Clinic fee shall be paid as clinic visits and procedures are performed
based on a scheduled visit fee of €40 and an unscheduled visit fee of €96.

 

(c) The Central Lab Fee shall be paid as clinic visits and procedures are
performed based on €26.40 per sample per antibody positive patient.

 

(d) Shipping shall be paid as a pass-through costs as incurred.

 

2

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

 

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

 

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

 

[remainder of this page intentionally left blank - signature page follows]

 

3

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

 

IN WITNESS WHEREOF the parties have caused this Amendment No.3 to be executed by
their respective duly authorized officers, and have duly delivered and executed
this Amendment No. 3 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

/s/ B. Nicholas Harvey

 

/s/ Bente Juel Riis

By: B.N. Harvey

By: Bente Juel Riis

Title: CFO

Title: CEO

 

 

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

 

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

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 4 TO WORK STATEMENT NB-1

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1, Amendment No. 2, and Amendment No. 3 to Work
Statement NB-1 as of December 9, 2011, June 18, 2012 and November 6, 2013
respectively, (as amended, “Work Statement NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 4 to Work Statement NB-1 (“Amendment No. 4”)
effective as of March 28, 2014 (“Amendment Date”). Capitalized terms used in
this Amendment No. 4 and not defined herein are used with the meanings ascribed
to them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 3, the parties agree as follows:

 

1. Addition of Performance Incentive Bonus Program (a) In order to facilitate
the timely completion of activities related to the Phase III clinical study of
the subcutaneous injection form of abaloparatide (formerly, BA058) under Work
Statement NB-1, Radius wishes to provide for an additional incentive payment of
up to $5 million to NB.

 

(b) A new section at the bottom Attachment B to Work Statement NB-1 (Budgets,
Fees, Pass-through Costs, and Payment Schedule*) is hereby amended to read in
full as follows:

 

After the Amendment Date, NB shall receive an additional fee of $500,000 for
every 50 subjects that complete End-of-Study visits and all procedures that are
required to be performed according to the Schedule of Visits and Procedures as
set out in Appendix 14.1 of the Protocol for the BA058-05-003 study (“Study
Completers”), subject to a maximum payment amount of $5 million (the
“Performance Incentive Bonus Program”).

 

(d) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new Paragraph (13) and
Paragraph (14) immediately following Paragraph (12) of the Payment Schedule,
which shall read in full as follows:

 

“(13)  In the event that an underwritten initial public offering of shares of
Radius’ common stock (an “IPO”) is consummated prior to May 31, 2014, the
purchase price for the Performance Incentive Bonus Program shall be paid solely
in cash. Payments will be made by Radius upon submission of an invoice by NB for
each group of 50 Study Completers until 450 subjects have completed and been
invoiced under the Performance Incentive Bonus Program. The final payment of
$500,000 for the last 50 Study Completers under the Performance Incentive Bonus
Program will be due up the completion of the last study subject for
BA058-05-003.

 

Should an IPO not be consummated by Radius prior to May 31, 2014, any payments
due under the Performance Incentive Bonus Program shall be instead be paid in
the form of Bonus Shares as part of the Bonus Equity Payment Amount in lieu of
cash under the same model as for Work Statement NB-1, NB-2 and NB-3 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.”

 

2.  Ratification.  Except to the extent expressly amended by this Amendment
No. 4, all of the terms, provisions and conditions of the Agreement and Work
Statement NB-1 are hereby ratified and confirmed and shall remain in full force
and effect.  The term “Work Statement NB-1”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-1 as amended by this
Amendment No. 4.

 

3.  General.  This Amendment No. 4 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument

 

[remainder of this page intentionally left blank - signature page follows]

 

1

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

 

IN WITNESS WHEREOF the parties have caused this Amendment No. 4 to be executed
by their respective duly authorized officers, and have duly delivered and
executed this Amendment No. 4 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

/s/ Robert E. Ward

 

/s/ Thomas Nielson

By:

Robert E. Ward

By:

Thomas Nielson

Title:

President and CEO

Title:

CFO

 

 

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

 

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

 

Execution Copy

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 5 TO WORK STATEMENT NB-1

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1, Amendment No. 2, Amendment No. 3 and Amendment
No. 4 to Work Statement NB-1 as of December 9, 2011, June 18, 2012, November 6,
2013 and March 28, 2014 respectively, (as amended, “Work Statement NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 5 to Work Statement NB-1 (“Amendment No. 5”)
effective as of May 19, 2014 (“Amendment Date”). Capitalized terms used in this
Amendment No. 5 and not defined herein are used with the meanings ascribed to
them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 5, the parties agree as follows:

 

1. Amendment of the IPO date. The latest date upon which an IPO is to be
consummated by Radius under Paragraph 13 and 14 of the Payment Schedule set
forth in Attachment B to Work Statement NB-1 is hereby amended from May 31, 2014
to June 30, 2014.

 

2.  Ratification.  Except to the extent expressly amended by this Amendment
No. 5, all of the terms, provisions and conditions of the Agreement and Work
Statement NB-1 are hereby ratified and confirmed and shall remain in full force
and effect.  The term “Work Statement NB-1”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-1 as amended by this
Amendment No. 5.

 

3.  General.  This Amendment No. 5 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument

 

IN WITNESS WHEREOF the parties have caused this Amendment No. 5 to be executed
by their respective duly authorized officers, and have duly delivered and
executed this Amendment No. 5 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

 

/s/ B.N. Harvey

 

/s/ Thomas Nielson

By: B.N. Harvey

 

By: Thomas Nielson

Title: CFO

 

Title: CFO

 

 

 

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

 

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

 

Execution Copy

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 6 TO WORK STATEMENT NB-1

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1, Amendment No. 2, Amendment No. 3, Amendment
No. 4 and Amendment No. 5 to Work Statement NB-1 as of December 9, 2011,
June 18, 2012, November 6, 2013, March 28, 2014 and May 19, 2014 respectively,
(as amended, “Work Statement NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 6 to Work Statement NB-1 (“Amendment No. 6”)
effective as of July 22, 2014 (“Amendment Date”). Capitalized terms used in this
Amendment No. 6 and not defined herein are used with the meanings ascribed to
them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 6, the parties agree as follows:

 

1. Reconciliation of costs related to clinical sites, renal CT and QCT scans and
Adjustment to Payment Schedule

 

(a) At Radius’ request, NB has previously initiated 4 additional non-CCBR sites
in Brazil (2), United States (1) and Hong Kong (1) and discontinued 3 non-CCBR
sites in Argentina (1), Brazil (1) and the US (1) in the clinical study that is
the subject of Work Statement NB-1. In addition, Radius has previously requested
NB to increase the number of renal CT scans to be obtained and analyzed and to
obtain new QCT scans (collectively, “A6 Services”). Radius wishes to now provide
for a reconciliation of payments to NB for these A6 Services under Work
Statement NB-1.

 

(b)  The NB representations and warranties set forth in Sections 8.2, 8.3, 8.5
and 8.6(ii) of the Agreement shall apply to the personnel, including the
Clinical Investigators, who perform the clinical study under the A6 Services. NB
shall be responsible for securing the applicable representations and warranties
from these clinical study sites and personnel, including Clinical Investigators.

 

(c)  The Study Assumptions table on the first page of Attachment A to Work
Statement NB-1 (Attachment 2 to the Agreement) is amended to reduce the total
Number of Sites from 42 to 28 reflecting this Amendment No. 6 as well as the
final number of sites, including deletion of sites in India that were not
initiated by Radius. As amended, the Study Assumptions table will read as
follows:

 

Protocol Number

 

BA058-05-003

Number of Sites:

 

28

Denmark

 

3

Estonia

 

2

Lithuania

 

1

Romania

 

1

Poland

 

6

Czech Republic

 

3

Brazil

 

5

Argentina

 

1

Hong Kong

 

1

USA

 

5

 

1

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

 

(d) The paragraph at the bottom Attachment B to Work Statement NB-1 (Budgets,
Fees, Pass-through Costs, and Payment Schedule*) is hereby amended to read in
full as follows:

 

“The pricing specified in this Budget is calculated based upon 2,040 subjects
randomized and completed at sites managed by NB, excluding sites in India and
the United State of America, and is not subject to any adjustment for the number
of patients to be Pre-screened/Advertisement, the screen failure rate after the
Patient Informed Consent has been signed, or the drop-out rate. However, this
Budget as well as the Bonus Equity Payment Amount under the Amended and Restated
Stock Issuance Agreement dated May 16, 2011 shall each be reduced by an amount
of €11,941 per subject for any subjects enrolled in India or the United States.
Such reduction to be applied in pro rata installments at the time of payment of
the Second Monthly Amount and the Third Monthly Amount. Otherwise, all pricing
will be adjusted on a pro rata fashion to reflect the actual study activities
completed by the study subjects.

 

For bone biopsies, this pro rata adjustment for biopsies less than or greater
than 200 shall be €4,153 for each bone biopsy at sites managed by NB and €2,008
for sites in India and the United State of America.

 

For obtaining of CT-scans, this pro rata adjustment for CT-scans less than or
greater than 300 shall be €610 for each CT-scan at sites managed by NB.

 

For CT-scans image analysis, this pro rata adjustment for CT-scans less than or
greater than 300 shall be €180 for each CT-scan for all sites. In addition,
there will be a charge of €4,134 for the first 100 Data Clarification Forms
(DCF) and €41 for each additional DCF greater than 100. In addition, there will
be a 10 per cent management charge to NB related to obtaining and the analysis
of CT-scans greater than 300.

 

For obtaining QCT-scans, the cost of €176,681 for 534 QCT-scans will be sent as
pass-through from Synarc, Inc. through NB and shall be adjusted on a pro-rata
basis for less than 534 QCT-scans. A separate amendment agreement will be
negotiated for QCT-scan image analysis between Radius and Synarc, Inc. which is
not included in the Amendment No. 6.

 

The following table related to the A6 Services is inserted immediately below the
above paragraph in Attachment B to Work Statement NB-1:

 

New sites:
Brazil (125, 126)
HK (182),
US (216)
Not active sites:
US (215)
Argentina (202)
Brazil (122)
Extra CT scan activity

 

Sponsor:

 

RADIUS

Protocol ID; 3 new sites

 

BA058-05-003

Development Phase:

 

III

Disease:

 

Osteoporosis

Site 126: Brazil; Dr. Albergaria

 

49

Site 125: Brazil; Dr. Borges

 

12

Site 182: Hong Kong; Dr. Liu Po Lung, Paul

 

0

Site 216 (US)

 

21

 

2

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

 

Number of sites in

 

3

Expected Date of FPFV:

 

Q3-2012

Preparation time

 

3

Expected Length of Recruitment (months):

 

2

Treatment Duration (months):

 

19

Close Out (months)

 

2

Total Study duration (Nordic involvement)

 

26

Number of Visits per patient

 

10

Number of patient visits

 

820

 

 

 

Responsibility

 

 

 

 

 

CRO - Task Description

 

Radius

 

Nordic

 

Total

 

Remarks

 

 

 

 

 

 

 

 

 

 

 

Project Coordination

 

 

 

 

 

 

 

 

 

Project Management

 

 

 

X

 

26,000

 

 

 

 

 

 

 

 

 

 

 

 

 

Prepare Study Materials

 

 

 

 

 

 

 

 

 

Informed Consent local version

 

 

 

X

 

0

 

 

 

Circulate source data and other documents

 

 

 

X

 

3,000

 

Site 125, 126, 216

 

 

 

 

 

 

 

 

 

 

 

Site Identification & Initiation Visits

 

 

 

 

 

 

 

 

 

Pre-Study feasibility

 

 

 

X

 

1,500

 

Site 182, 125, 126

 

Site Identification

 

 

 

X

 

1,500

 

Site 182, 125, 126

 

Site Selection Visits

 

 

 

X

 

9,000

 

Site 182, 125, 126

 

Site Initiation Visits

 

 

 

X

 

9,000

 

Site 125, 126, 216

 

Prepare site contracts

 

 

 

X

 

3,000

 

Site 182, 125, 126

 

Administration of Site payment (including calcium/D suppl)

 

 

 

X

 

2,000

 

Site 125, 126

 

 

 

 

 

 

 

 

 

 

 

Study Start-up Activities

 

 

 

 

 

 

 

 

 

Set-up Investigators Study File

 

 

 

X

 

600

 

Site 125, 126, 216

 

 

 

 

 

 

 

 

 

 

 

Regulatory

 

 

 

 

 

 

 

 

 

Submission to EC and RA; Brazil - 2 sites

 

 

 

X

 

38,625

 

Site 125, 126

 

Submission to EC and RA; Hong Kong

 

 

 

X

 

5,000

 

Site 182

 

 

 

 

 

 

 

 

 

 

 

Study Drug

 

 

 

 

 

 

 

 

 

Coordinate Drug Shipment to sites

 

X

 

X

 

2,600

 

 

 

 

3

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

 

Discount

 

 

 

 

 

-1,300

 

For site 202 and 215 not active

 

IVR training

 

X

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Pharmacovigilance

 

 

 

 

 

 

 

 

 

Extra PV management time

 

 

 

X

 

7,800

 

 

 

Discount

 

 

 

 

 

-2,600

 

For site 202 and 215 not active

 

 

 

 

 

 

 

 

 

 

 

Data Management / EDC

 

 

 

 

 

 

 

 

 

Add sites to EDC System

 

 

 

X

 

30,000

 

Site 125, 126, 216

 

Site Installation & Training for EDC

 

 

 

X

 

3,000

 

Site 125, 126, 216

 

Data Management

 

 

 

X

 

52,000

 

 

 

Discount

 

 

 

 

 

-26,000

 

For site 202 and 215 not active

 

 

 

 

 

 

 

 

 

 

 

Monitoring and site Administration

 

 

 

 

 

 

 

 

 

Extra fee to external CRO (Quintiles)

 

 

 

X

 

131,331

 

Site 125, 126 discounted for all site 202 activity

 

US site 216

 

 

 

X

 

50,000

 

 

 

Discount

 

 

 

 

 

-45,000

 

For site 215 not active

 

Site Contact & Administration

 

 

 

X

 

54,600

 

Site 125, 126, 216

 

Discount

 

 

 

 

 

-18,200

 

For site 215 not active

 

Audits

 

 

 

X

 

9,000

 

Site 125, 126, 216

 

 

 

 

 

 

 

 

 

 

 

Close-Out

 

 

 

 

 

 

 

 

 

Close-Out Visits

 

 

 

X

 

9,000

 

Site 125, 126, 216

 

Discount

 

 

 

 

 

-3,000

 

For site 215 not active

 

Final Archiving (to be negotiated separately)

 

 

 

 

 

0

 

 

 

 

 

 

 

 

 

 

 

 

 

Synarc Research Laboratory

 

 

 

 

 

99,450

 

Extra lab kits and project management; shipment as pass through

 

 

 

 

 

 

 

 

 

 

 

1.TOTAL (EURO)

 

 

 

 

 

425,906

 

 

 

 

4

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

 

Start-up Cost for the new HK site

 

Equipment

 

Cost (HKD)

 

Remarks

 

 

 

 

 

Centrifuge

 

75,000.00

 

Eppendoff

 

1 TOTAL

 

€

425,906.15

 

ECG

 

25,000.00

 

Schiller AG

 

2 TOTAL

 

€

16,353.00

 

Refrigerator 4oC

 

8,000.00

 

Non-medical

 

3 TOTAL

 

€

215,016.69

 

Freezer -18 to -20oC

 

10,000.00

 

Non-medical

 

PASS-THROUGH

 

€

176,680.92

 

Thermometer (x3)

 

1,050.00

 

HKD350 each

 

TOTAL

 

€

833,956.76

 

Printer

 

3,000.00

 

 

 

 

 

 

 

Internet 10G with emergency phone number

 

6,000.00

 

USB HKD400/ month

 

 

 

 

 

Balance

 

2,980.00

 

Charder MS4900

 

 

 

 

 

Standiometer

 

18,500.00

 

Holtain

 

 

 

 

 

WelchAllyn Connex ProBP Monitor

 

7,000.00

 

 

 

 

 

 

 

2. TOTAL

 

163,530

 

€

16,353.00

 

 

 

 

 

 

CT - Service

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

QCT up to 300 scans:

 

$

211,304.00

 

Pass-Through

 

 

 

 

 

QCT from 300 to 534:

 

$

15,210.00

 

Pass-Through

 

 

 

 

 

CT up to 300 scans:

 

$

0.00

 

 

 

 

 

 

 

CT from 300 to 534:

 

$

245,302.20

 

 

 

 

 

 

 

Additional DCF’s:

 

$

5,300.00

 

 

 

 

 

 

 

SubTotal (USD)

 

$

250,602.20

 

 

 

 

 

 

 

Nordic Management Fee 10%

 

$

25,060.22

 

 

 

 

 

 

 

PASS-THROUGH (QCT)

 

$

226,514.00

 

€

 176,680.92

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Total

 

$

275,662.42

 

€

 215,016.69

 

 

 

 

 

 

(e) The “Payment Schedule” set forth in Attachment B to Work Statement NB-1
(Attachment 2 to the Agreement) is amended to add a new Paragraph (15)
immediately following Paragraph (14) of the Payment Schedule, which shall read
in full as follows:

 

“(15) The total purchase price for the A6 Services shall be €833,957 assuming
534 CT and QCT scans are completed under this Amendment No. 6 and shall be paid
solely in cash denominated in euros, as follows:

 

(a)  €326,456 for the net extra site activities

 

(b) €99,450 for extra lab kits, project management and shipment as a pass
through

 

(c) €16,353 for the start-up costs for the additional Hong Kong site.

 

(d) €215,017 for obtaining and analysis of the additional CT scans greater than
300 including the NB management fee.

 

(e) €176,681 for obtaining the additional QCT scans.

 

Radius shall pay NB €376,968 of these incremental fees within 15 days of the
effective date representing (i) €261,165 equal to 80 per cent of the net extra
site activities; plus (ii)  the total Hong Kong start-up costs of €16,353; plus
(iii) €99,450 for the extra lab kits and project management. Radius shall pay NB
for the shipments costs as pass-through costs as incurred. Radius shall pay NB
the balance for obtaining and analyzing the additional CT-scans and for
obtaining the QCT-scans as well as any additional DCF and shipments costs as
pass-through costs as incurred. Radius shall pay the balance of costs for the A6
Services of €65,291 when the study database for the clinical study that is the
subject of Work Statement NB-1 is locked and transferred to Radius”

 

(g)  The “Trial Activities and Delegation of Responsibilities” table set forth
in Attachment C to Work Statement NB-1 (Attachment 2 to the Agreement), as
amended, shall apply to New Sites managed by NB.

 

5

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

 

2.  Ratification.  Except to the extent expressly amended by this Amendment
No. 6, all of the terms, provisions and conditions of the Agreement and Work
Statement NB-1 are hereby ratified and confirmed and shall remain in full force
and effect. The term “Work Statement NB-1”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-1 as amended by this
Amendment No. 6.

 

3.  General.  This Amendment No. 6 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument

 

[remainder of this page intentionally left blank - signature page follows]

 

6

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

 

IN WITNESS WHEREOF the parties have caused this Amendment No.6 to be executed by
their respective duly authorized officers, and have duly delivered and executed
this Amendment No. 6 under seal as of the Amendment Date.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL DEVELOPMENT VII A/S

 

 

 

/s/ Robert E. Ward

 

/s/ Jeppe Ragnar Andersen

By: R. E. Ward

 

By: Jeppe Ragnar Andersen

Title: President & CEO

 

Title: CEO

 

 

 

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

 

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

 

Execution copy

 

CLINICAL TRIAL SERVICES AGREEMENT AMENDMENT NO. 7 TO WORK STATEMENT NB-1

 

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 the
certain Clinical Trial Services Agreement (“Agreement”) and that certain Work
Statement NB-1 under the Agreement as of March 29, 2011 (“Effective Date”), and
entered into an Amendment No. 1, Amendment No. 2, Amendment No. 3, Amendment
No. 4, Amendment No. 5, and Amendment No. 6 to Work Statement NB-1 as of
December 9, 2011, June 18, 2012, November 6, 2013, March 28, 2014, May 19, 2014
and July 22, 2014 respectively, (as amended, “Work Statement NB-1”).

 

Pursuant to Section 2.3, 2.11 and 11.7 of the Agreement, the parties wish to
enter into this Amendment No. 7 to Work Statement NB-1 (“Amendment No. 7”)
effective as of July 22, 2014 (“Amendment Date”).  Capitalized terms used in
this Amendment No. 7 and not defined herein are used with the meanings ascribed
to them in the Agreement and Work Statement NB-1.

 

NOW THEREFORE, in consideration of the mutual covenants and promises contained
in this Amendment No. 7, the parties agree as follows:

 

1. Addition of SAE Narrative Writing and Review (a) At Radius request and
direction, NB will assign qualified personnel to write Serious Adverse Event
(SAE) narratives and perform SAE narrative review for BA058-05-003 according to
version 1 of the narrative writing procedures agreed upon May 23rd, 2014.

 

(b) A new section at the bottom Attachment B to Work Statement NB-1 (Budgets,
Fees, Pass-through Costs, and Payment Schedule) is hereby amended to read in
full as follows:

 

Budget

 

Euro

 

SAE Narrative writing (each)

 

€

115

 

SAE Narrative review (each)

 

€

60

 

 

“The price per narratives written is €115, and the price per narrative review is
€60, paid by invoice on a quarterly basis based on actual work performed.”

 

2.  Ratification.  Except to the extent expressly amended by this Amendment
No. 7, all of the terms, provisions and conditions of the Agreement and Work
Statement NB-1 are hereby ratified and confirmed and shall remain in full force
and effect.  The term “Work Statement NB-1”, as used in the Agreement, shall
henceforth be deemed to be a reference to Work Statement NB-1 as amended by this
Amendment No. 7.

 

3.  General.  This Amendment No. 7 may be executed in counterparts, each of
which will be deemed an original with all such counterparts together
constituting one instrument.

 

[remainder of this page intentionally left blank - signature page follows]

 

1

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

 

IN WITNESS WHEREOF the parties have caused this Amendment No. 7 under Work
Statement NB-1 to be executed by their respective duly authorized officers, and
have duly delivered and executed this Amendment No. 7 under seal as of the
Amendment Date.

 

 

RADIUS HEALTH, INC.

 

NORDIC BIOSCIENCE CLINICAL
DEVELOPMENT VII A/S

 

 

 

 

 

 

/s/ Robert E. Ward

 

/s/ Jeppe Ragnar Andersen

By: R.E. Ward

 

By: Jeppe Ragnar Andersen

Title: President & CEO

 

Title: CEO

 

 

 

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 & CEO

 

Attn: CEO

Phone: 01.617.551.4700

 

Phone: 45.4452.5251

Fax: 01.617.551.4701

 

Fax: 45.4452.525

 

2

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