THE GENERAL HOSPITAL CORPORATION
CLINICAL TRIAL AGREEMENT
(Investigator-Initiated)
This Clinical Trial Agreement ("Agreement") is made as of the 28 day of
September, 2009 ("Effective Date") between CytoDyn, Inc., a publicly traded
corporation organized under the laws of Colorado with its principal place of
business at 0000 Xxxxx Xxxxxx, Xxxxx Xx, Xxx Xxxxxx 00000 ("Company"), and The
General Hospital Corporation d/b/a Massachusetts General Hospital, a
not-for-profit corporation organized under the laws of Massachusetts with its
principal place of business at 00 Xxxxx Xxxxxx, Xxxxxx, XX 00000
("Institution"), each referred to herein individually as a "Party" and
collectively as the "Parties."
The Parties to this Agreement share a common mission of improving the
public health by engaging in research for the purpose of discovering and making
available to the public new and improved medical drugs, devices, procedures, and
information. In connection with this mission, Institution, through Xxxx
Xxxxxxxxx, M.D. ("Principal Investigator"), having particular expertise and
opportunity, proposes to provide, and Company desires to have, further research
conducted on Company's drug described below.
Accordingly, for good and valuable consideration, the sufficiency of
which is hereby acknowledged, the Parties agree as follows:
Section 1: Study Performance
----------------------------
1.1 Conduct of Study in Accordance with Protocol; Priority of Terms.
Subject to the initial and continuing approvals described in Section 1.2 below,
Institution, through Principal Investigator, agrees to conduct an ex-vivo study
of Cytolin(R) brand of S6FI monoclonal antibodies ("Study Drug") in accordance
with the study protocol entitled "An observational study to determine the
in-vitro immunologic and virology activity of Cytolin," attached to this
Agreement as Exhibit A and herein incorporated by reference ("Study"). The
Parties agree that the Study will be performed in strict accordance with the
Study protocol entitled above, and any subsequent amendments thereto (the" Study
Protocol"). In the event of any conflict between the Protocol and the provisions
of the main body of this Agreement, the Protocol shall govern with respect to
scientific and subject consent issues, and the provisions of the main body of
this Agreement shall govern with respect to all other issues. In the event of
any conflict between the Study informed consent form and the provisions of this
Agreement with respect to any commitment by Company to cover costs associated
with subject injuries, the broader commitment (the commitment that is more
protective of human subjects) shall control.
1.2 Study Review and Approvals. The Study shall be conducted by
personnel, agents, vendors, or consultants of Institution under the direction of
the Principal Investigator at Institution or additional facilities with the
prior approval and ongoing review of all appropriate and necessary review
authorities. Institution, through Principal Investigator, shall provide Company
with written evidence of review and approval of this Study by Institution's
Institutional Review Board ("IRB") prior to the initiation of the Study and
shall inform Company of the IRB's continuing reviews of the Study promptly after
each such review takes place, which shall be at least once per year. Initiation
of the Study Protocol shall not begin until IRB approval
is obtained. In accordance with the obligations under the Food and Drug
Administration Amendment Act of 2007 ("the Act"), Company agrees to fully
register this Study with the public registry xxxxxxxxxxxxxx.xxx before
enrollment of the first patient at Institution and comply with all of the Act's
requirements thereafter.
1.3 Completion of the Study. For purposes of this Agreement, Company
and Institution shall consider the Study to be complete and concluded at all
sites at such time as the occurrence of final data lock or earlier termination
by a Data Safety Monitoring Board or as otherwise specified in the Protocol
("Study Conclusion").
1.4 Provision and Use of Study Drug. Company shall be responsible for
providing and delivering to Institution, at no charge, such quantities of the
Study Drug in bags for in vitro use as needed for conducting the Study in
accordance with the Study Protocol, along with the results of safety testing for
the lot of Study Drug provided, and conducted according to currently published
standards. Institution acknowledges receipt of the latter. Company understands
that Institution and Principal Investigator are relying on timely delivery of
the Study Drug in order for Institution to perform its obligations under this
Agreement. Institution understands that the ability of the Company to provide
the drug depends upon Institution providing shipping and delivery requirements.
Institution, through Principal Investigator, will safeguard such Study Drug with
the degree of care used for its own property and shall return or otherwise
dispose of any remaining Study Drug at the Study Conclusion in accordance with
the Study Protocol. Institution and Principal Investigator shall not use any
Study Drug for any purpose other than the Study, unless otherwise agreed.
Company represents and warrants that it is in compliance with federal, state,
and local laws and regulations relating to the manufacture and formulation of
any investigational drug and to other materials supplied, and with other
applicable legal requirements.,
1.5 Compliance with Applicable Laws and Regulations. Parties agree to
conduct the Study in accordance with all applicable local, state, and federal
laws and regulations.
Section 2: Material Subject Information
---------------------------------------
2.1 Company agrees to notify Principal Investigator in writing
promptly and at least within fifteen (15) days of information (such as Study
results) that could affect the safety or medical care of current or former
subjects, affect current subjects' willingness to continue participation,
influence the conduct of the Study, or alter the IRB's approval. Company and
Institution shall comply with their respective reporting requirements to
regulatory authorities, including, for example, the Food and Drug
Administration, the Office for Human Research Protections, and other authorities
as required. Institution, through the Principal Investigator and/or IRB as
appropriate, shall be responsible for informing subjects of the above important
information they learn from Company in accordance with the IRB-approved informed
consent form and Company shall not contact them. No other provision of this
Agreement shall be construed to override the provisions of this Section 2.1.
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Section 3: Study Data/Results
-----------------------------
3.1 Provision of Data/Results; Provision of Abstracts/Manuscripts].
(a) Institution shall own the data resulting from the Study.
Institution shall provide copies of the data produced in the performance of the
Study to Company. Company may use the Study data in accordance with Section 3.2.
(b) All data from laboratory analyses for Institution's Study subjects
which are performed off-site, and all other subject-specific data generated by
Company or its agents for Institution's Study subjects, if Institution does not
receive such data directly from the off-site laboratory or other source, shall
be provided by Company to Institution upon the Study Conclusion. If the Study is
blinded, Company shall also provide the randomization codes for Institution's
Study subjects upon the Study Conclusion.
3.2 Use of Data/Results. Institution shall comply in all material
respects with all applicable federal, state and local laws and regulations
regarding the privacy of individually identifiable health information (including
its collection, use, storage, and disclosure), including, but not limited to,
the Health Insurance Portability and Accountability Act of 1996 ("HIP AA") and
the regulations promulgated thereunder, as may be amended from time to time.
Company agrees to collect, use, store, and disclose individually identifiable
health information collected or produced in the Study only for the purpose of
the Study and related studies (that is, other studies of the Study Drug, alone
or in combination with other drugs, or other studies that relate to the medical
condition or disease area under investigation in the Study), and for the purpose
of complying with applicable law, provided that all such uses are disclosed in
the IRB-approved informed consent form. If Institution's IRB-approved informed
consent form so states, Company may use information that is not identifiable
under any applicable U.S. laws for any research and development purpose. Company
will use all reasonable efforts to protect the privacy and security of
individually identifiable health information and will require its business
partners to do so also. Company will not contact any Study subjects, unless
permitted by the informed consent form. No other provision in this Agreement
shall be construed to override the provisions of this Section 3.2.
3.3 Use of Specimens/Tissue. Company will collect, use, store, and
disclose any specimens/tissue it receives only in accordance with the Protocol
and informed consent form, and in any event will not collect, use, store, or
disclose any individually identifiable health information attached to or
contained within the specimens/tissue in any manner that would violate Section
3.2 of this Agreement.
Section 4: Publication
----------------------
4.1 Principal Investigator shall be free to publish the data/results
from the Study in accordance with this Section 4.1.] Principal Investigator
shall be free to publish the data/results of the Study subject only to the
provisions of Section 8 regarding Company's Proprietary
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Information. The Institution shall require Principal Investigator to furnish
Company with a copy of any proposed publication prior to submission for
publication, at least thirty (30) days prior to submission for manuscripts and
at least seven (7) days prior to submission for abstracts. Company shall be
entitled to review such proposed publications solely for the purpose of
identifying Company Proprietary Information, which shall be removed from the
publication upon Company's request; and to identify any patentable Inventions,
which shall be addressed as described below; and to provide any other comments
Company desires to provide, provided that Principal Investigator shall have no
obligation to address any such additional comments. At the expiration of such
thirty (30) day or seven (7) day period, Principal Investigator may proceed with
submission for publication provided that any identified Company Proprietary
Information has been removed; and provided further that upon notice by Company
that Company reasonably believes a patent application claiming an Invention (as
defined in Section 5) should be filed prior to such publication, in
Institution's discretion such submission shall be delayed for up to an
additional thirty (30) days or until any patent application or applications have
been filed, whichever shall first occur. In no event shall the submission of
such publication of results be delayed for more than sixty (60) days for
manuscripts and for more than thirty-seven (37) days for abstracts from the date
such proposed publication was provided to Company; at the end of said sixty (60)
or thirty-seven (37) days, the Principal Investigator shall be free to publish
such results as proposed.
Section 5: Inventions/Intellectual Property
-------------------------------------------
5.1 The Principal Investigator and any other investigators
(hereinafter "Institution Investigator") who shall conceive and reduce to
practice an invention, solely or jointly, in the performance of the Study as
outlined in the Protocol (hereinafter referred to as "Invention") shall promptly
report such Invention to Institution and shall assign all of his or her rights,
title and interest in the Invention to Institution. Institution shall promptly
advise Company in writing of each Invention disclosed to Institution and shall
discuss with Company whether a patent application or applications (hereinafter
referred to, together with any patents issued thereon, as "Patent Rights")
pertaining to such Invention should be filed and in which countries. In the
event of joint inventorship between Company personnel and Institution
Investigator, Company personnel shall assign all of their rights, title and
interest in the Invention ("Joint Invention") to Company, and Institution
Investigator shall assign all of their rights, title and interest in the Joint
Invention to Institution, and the Joint Invention will be deemed to be jointly
owned. If both parties mutually agree that Patent Rights should be filed,
applications assigned solely to Institution shall be filed by Institution, and
applications owned jointly by Institution and Company shall be filed as mutually
agreed upon by the parties. In the event Company is not interested in having
Patent Rights filed with respect to a particular Invention, Company shall advise
Institution of such fact within ninety (90) days from the date on which the
Invention was disclosed to Company by Institution and Institution shall be free
to file and prosecute Patent Rights on such Invention (including Institution's
rights in any Joint Invention) at its own expense and to license such Patent
Rights to any other party.
5.2 All patent costs pertaining to any Patent Rights filed by mutual
agreement of Company and Institution, including preparation, filing,
prosecution, issuance and maintenance costs, shall be borne by Company.
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Page 4 of 19
5.3 As to any Patent Rights assigned in whole or in part to
Institution and filed by mutual agreement of the parties, Company shall have for
the three (3) months next following the filing of such Patent Rights in the
United States Patent and Trademark Office the option to negotiate a world-wide,
royalty bearing, exclusive license under the rights assigned by an Institution
Investigator to Institution therein with the right to sublicense. It is
understood that Institution will reserve the right to use any Invention for
research, clinical and educational purposes, and that if federal funding has
supported the Invention, Company's license will be subject to the rights,
conditions and limitations imposed by United States law with respect to Subject
Inventions (as defined in 35 U.S.C. Section 202 et seq., as amended), including
without limitation the royalty-free non-exclusive license granted to the United
States Government with respect to such Subject Inventions (see 35 USC Section
202 et seq., as amended, and regulations pertaining thereto).
5.4 This option is to be exercised by written notice to Institution
during said three month period and the negotiation, during the three (3) months
next following such notice, of a license agreement containing license terms
standard for agreements between universities and industry including without
limitation clauses providing for payment of reasonable royalties and other
compensation to Institution, objective, time-limited due diligence provisions
for the development, commercialization and marketing of a product embodying the
Invention and product liability indemnification and insurance requirements which
are acceptable to Institution's liability insurance carrier. In the absence of
such notice by Company and agreement on license terms, Institution may grant a
license to such Patent Rights to any other party.
5.5 All information given to Company by Institution in accordance with
Sections 5.1, 5.2, 5.3, and 5.4 will be held in confidence by Company so long as
such information remains unpublished or publicly undisclosed by Institution.
Section 6: Use of Name
----------------------
6.1 Except for disclosure by Institution of Company's support for the
Study in publications, for purposes of recruitment/consent of Study subjects,
and by either Party for purposes of meeting any applicable requirements for the
registration of the Study or of Study results with a publicly accessible or
other clinical trial registry, and for satisfying the Company's obligation to
report its financial commitments to Institution in cash or in kind and related
material events in an 8K filed with the Securities and Exchange Commission
within four days of the date this Agreement is executed, neither Party to this
Agreement shall use the name of the other Party or of any staff member,
employee, student, or agent of the other Party or any adaptation, acronym or
name by which the other Party is commonly known, in any advertising, promotional
or sales literature or in any publicity without the prior written approval of
the Party or individual whose name is to be used., which approval shall not be
unreasonably withheld.
Section 7: Study Records
------------------------
7.1 Institution shall make Study records (including minimum necessary
portions of
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medical records) available to Company representatives upon reasonable request
for comparison with case report forms. Any audits conducted by Company will be
undertaken in conjunction with Institution, at reasonable times and with
reasonable prior notice, and pursuant to guidelines established by Institution
in order to assure patient confidentiality. Each of Company and Institution
shall retain records of the Study, including in Institution's case either the
original or a copy of all volunteer consent forms, in conformance with federal
regulations applicable to it. . Institution shall also make such records
available upon request for review by representatives of the U.S. Food and Drug
Administration. Company acknowledges that Company may not direct the manner in
which Institution fulfills its obligations to permit inspection by governmental
entities. It shall not be a breach of this Agreement for Institution to comply
with the demands and requests of any governmental entity in accordance with
Institution's judgment or to fail to inform and consult with the Company before
complying with such demand or request.
Section 8: Proprietary Information
----------------------------------
It is anticipated that in the performance of this Agreement, Principal
Investigator, Company and Institution may need to disclose to each other
information, which is considered confidential. The rights and obligations of the
parties with respect to such information are as follows:
8.1 "Disclosing Party" shall mean a party that discloses Proprietary
Information (as defined in paragraph 8.2 below) under this Agreement. "Receiving
Party" shall mean a party that receives Proprietary Information under this
Agreement.
8.2 "Proprietary Information" refers to information of any kind, other
than data from or results of the Study, which is obtained by Receiving Party
from Disclosing Party, which, by appropriate marking, is identified as
confidential and proprietary at the time of disclosure. In the event that
Proprietary Information must be provided visually or orally, obligations of
confidence shall attach only to that information which is confirmed by
Disclosing Party in writing within thirty (30) working days as being
confidential.
8.3 Period of Restriction. For a period of five (5) years after the
Effective Date of this Agreement and indefinitely with respect to any
individually identifiable health information, institutional billing information
and institutional financial information disclosed by Institution to Company,
Receiving Party agrees to use reasonable efforts, no less than the protection
given their own confidential information, to use Proprietary Information
received from Disclosing Party and accepted by Receiving Party only in
accordance with this Section 8.
8.4 Use of Proprietary Information. Receiving Party agrees to use
Disclosing Party's Proprietary Information solely for the purposes of conducting
the Study, obtaining any required review of the Study or its conduct, or
ensuring proper medical treatment of any patient or subject. Receiving Party
agrees to make Proprietary Information available only to those personnel and
agents at Receiving Party and those consultants and vendors who require access
to it in the performance of this Study and to inform them of the confidential
nature of such information.
8.5 Release of Proprietary Information. Except as provided herein,
Receiving Party
Clinical Trial Agreement
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agrees to keep all Proprietary Information confidential unless Disclosing Party
gives specific written consent for release.
8.6 Notice of Unauthorized Disclosure. Receiving Party shall notify,
and shall require any recipient to notify, Disclosing Party of any disclosure
not authorized hereunder of which it becomes aware. In such situations,
Receiving Party shall take and shall require each such recipient to take
reasonable steps to prevent any further disclosure or unauthorized use.
8.7 Exclusions. No Receiving Party shall be required to treat any
information as Proprietary Information under this Agreement in the event:
(i) it is publicly available prior to the date of the Agreement or
becomes publicly available thereafter through no wrongful act of
Receiving Party;
(ii) it was known to Receiving Party prior to the date of disclosure or
becomes known to Receiving Party thereafter from a third party
having an apparent bona tide right to disclose the information;
(iii) it is disclosed by Receiving Party in accordance with the terms of
Disclosing Party's prior written approval;
(iv) it is disclosed by Disclosing Party without restriction on further
disclosure;
(v) it is independently developed by Receiving Party; or,
(vi) Receiving Party is obligated to produce it pursuant to a
requirement of applicable law or an order of a court of competent
jurisdiction or a facially valid administrative, Congressional or
other subpoena, provided that the Receiving Party, subject to the
requirement or order or subpoena (A) promptly notifies Disclosing
Party and (B) cooperates reasonably with Disclosing Party's
efforts to contest or limit the scope of such disclosure.
8.8 Each party reserves the right, in its sole discretion and without
prior notice to any other party, to disclose its own Proprietary Information to
any third party for any purpose.
Section 9: Budget and Payments
------------------------------
9.1 General. Company agrees to support this Study with a research
grant of three hundred sixteen thousand seven hundred and fifty-five Dollars
($316,755.00), inclusive of indirect costs, 50% to be paid upon execution of
this Agreement, 25% to be paid by month three of the study, and 25% to be paid
by month six of the study, all subject to the internal-controls provisions of
the Xxxxxxxx-Xxxxx Act.
9.2 Checks. Checks shall be made payable to The General Hospital
Corporation, Federal Tax ID No.: 00-0000000, shall reference the name of the
Principal Investigator, the Protocol number, and the Research Management
agreement number 2009A055353, and shall be
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forwarded to:
Massachusetts General Hospital
Research Finance
XX Xxx 000000
Xxxxxx, XX 00000-0000
9.3 IRB Fee. Company shall pay a one-time, non-refundable,
non-overhead-bearing fee of twenty five hundred dollars ($2,500.00) to
Institution to cover its IRB's costs for reviewing the initial Protocol and any
subsequent annual reviews that may be required. Institution shall invoice
Company for this fee upon execution of this Agreement.
Section 10: Term and Termination
--------------------------------
10.1 Term. The term of this Agreement shall be from the Effective Date
until completion of the Parties' substantive obligations under the Agreement in
the performance of the Study, unless earlier terminated in accordance with
Section
10.2 Termination.
(a) Either Party hereto shall have the right to terminate the Study
and this Agreement at any time upon six (6) months prior written notice thereof
to the other Party, except that either Party may terminate the Study and this
Agreement at any time upon thirty (30) days prior written notice thereof to the
other Party in the event of a material breach of the Agreement by the other
Party, and except that either Party may terminate the Study and this Agreement
immediately upon written notice to the other Party if necessary to protect the
health, welfare or safety of any Study subject.
(b) If the Principal Investigator ceases to serve in such role during
the term of the Agreement, Institution shall promptly notify Company.
Institution may name a substitute principal investigator (who shall thereafter
be referred to as Principal Investigator for purposes of this Agreement),
subject to the approval of Company, which approval will not be unreasonably
withheld by the Company. If the Parties fail to reach agreement with respect to
continuation of the Study and the Agreement within ninety (90) days following
the date on which Institution notifies Company that the original Principal
Investigator became unavailable, Company shall have the right to terminate the
Study and this Agreement immediately upon written notice to Institution.
10.3 Continuation of Enrolled Subjects. The Parties agree that if, at
the time either Party receives notice of termination pursuant to this section,
any subjects are enrolled in the Study, said subjects shall complete the Study,
at Company's expense, if completion is in the best interest of said subjects.
10.4 Continuation of Grant/Payments. In the event of any termination
other than a for-
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cause termination by Company for Institution's material breach, the amount of
the research grant by Company to support the Study shall be appropriately
prorated to allow Institution to recover reasonable costs and noncancellable
commitments incurred, including without limitation, termination salary costs of
any Institution personnel released as a result of such termination, and other
payments payable by Company for procedures or portions of procedures completed
at the time of termination shall be made/fulfilled.
10.5 Survival. The obligations of the Parties under Sections 1.1
(Priority), 1.3, [1.4,] 2.1, 3.1, 3.2, 3.3, 4.1, 5.1-5.5, 6.1, 7.1, 8.1-8.8,
10.3, 10.4, 11.1, 11.2, 11.3, 12.1, 13.2, and 13A13.8 shall survive any
termination or expiration of this Agreement.
Section 11: Subject Injury; Insurance; Coordination with Other Agreements
--------------------------------------------------------------------------
11.1 Injury.
(a) Company agrees to reimburse Institution for (or otherwise pay for)
the care and treatment of any illness or injury occurring to a person involved
in the Study resulting from their participation in the Study.
(b) Company represents and warrants that it will not allow any Company
representative or agent to insert or negotiate into the Study's informed consent
form any language whatsoever.
(c) Company's commitment under (a) above shall not apply to any
illness or injury to the extent it directly results from: (i) the negligence or
reckless or intentional misconduct of, or violation of law by, Institution,
Principal Investigator, or Institution's personnel; or (ii) failure of
Institution, Principal Investigator, or Institution's personnel to adhere to the
terms of the Protocol for the Study, provided, however, that emergency medical
care shall not be deemed a violation of the Protocol.
11.2 Insurance.
(a) Company shall, at its sole cost and expense, procure and maintain
policies of general liability insurance in amounts not less than Two Million
Dollars ($2,000,000) per occurrence and Two Million Dollars ($2,000,000) annual
aggregate covering its obligations under this Agreement, including contractual
liability coverage for injury under this Section 11, if any.
(b) Company shall provide Institution at its request with written
evidence of such insurance prior to the commencement of the Study. Company shall
provide Institution with written notice at least thirty (30) days prior to the
cancellation, non-renewal or material change, in such insurance; if Company docs
not obtain replacement insurance providing comparable coverage within such
thirty- (30-) day period, Institution shall have the right to terminate this
Agreement effective at the end of such thirty- (30-) day period without notice
of any additional waiting periods.
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11.3 Coordination with Other Agreements. The Parties do not intend any
provision in this Agreement concerning insurance commitments or indemnification
commitments (if any) to affect or be affected by any additional insurance or
indemnification commitments that may be provided for in any separate contract,
purchase order, terms and conditions document, or other agreement between the
Parties related to the Study (including agreements related to the purchase,
lease, or use of any Study Equipment).
Section 12: Notices
-------------------
12.1 Any written notices, reports, correspondences or other
communications required under or pertaining to this Agreement shall be given by
prepaid, first class, registered or certified mail or by an express/overnight
delivery service provided by a commercial carrier, properly addressed as
follows:
Xxxxx XxXxxxx, X.X., Pharm.D.
Agreement Associate
Partners Clinical Research Xxxxxx
000 Xxxxxxxxxx Xxxxxx, 0xx Xxxxx
Xxxxxx, XX 00000
Xxxx Xxxxxxxxx, M.D.
Massachusetts General Hospital
00 Xxxxx Xx.
Xxxxxx, XX 00000
Xxxxx X. Xxxxx
CytoDyn, Inc.
0000 Xxxxx Xxxxxx
Xxxxx Xx, Xxx Xxxxxx 00000
Section 13: Miscellaneous
-------------------------
13.1 Amendment. The terms of this Agreement can be modified only by a
writing, which is signed by authorized representatives of Institution and
Company.
13.2 Choice of Law; Jurisdiction and Venue. This Agreement shall be
governed by and construed and interpreted in accordance with the laws of the
Commonwealth of Massachusetts. Each Party agrees to submit to the exclusive
jurisdiction of the Superior Court for Suffolk County, Massachusetts, and the
United States District Court for the District of Massachusetts with respect to
any claim, suit, or action in law or equity arising in any way out of this
Agreement or the subject matter hereof.
13.3 Assignment. Neither Party to this Agreement may assign its
obligations hereunder without the prior written consent of the other Party.
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13.4 Entire Agreement. This Agreement, including any exhibits,
attachments, and other documents that are incorporated by reference herein,
constitutes the entire understanding and agreement between the Parties, and
supersedes and replaces all prior agreements, understandings, writings and
discussions between the Parties with respect to the subject matter of this
Agreement.
13.5 Waiver. The failure of a Party in any instance to insist upon the
strict performance of the terms of this Agreement shall not be construed to be a
waiver or relinquishment of any of the terms of the Agreement, whether at the
time of the Party's failure to insist upon strict performance or at any time in
the future, and such term(s) shall continue in full force and effect.
13.6 Severability. Each clause of this Agreement is a distinct and
severable clause and if any clause is deemed illegal, void, or unenforceable,
the validity, legality, or enforceability of any other clause of this Agreement
will not be affected thereby.
13.7 Additional Partners HealthCare Hospital Site. In the event that an
additional Partners HealthCare hospital becomes an enrolling site for this
Study, then the Sponsor agrees that the substantive terms of the clinical trial
agreement with the additional Partners HealthCare hospital will be the same as
in this Agreement except with respect to budget and contracting party.
13.8. Titles. All the titles and headings contained in the Agreement are
inserted only as a matter of convenience and reference and do not define, limit,
extend, or describe the scope of this Agreement or the intent of any of its
provisions.
13.9 Counterpart Signatures. This Agreement may be executed in one or
more counterparts, each of which counterpart shall be deemed an original
Agreement and all of which shall constitute but one Agreement.
13.10 No Agency. Joint Venture or Partnership. Each Party's relationship
to the other Party under this Agreement will be that of an independent
contractor and neither Party shall be considered to be an agent, joint venturer
or partner of the other Party.
IN WITNESS WHEREOF, the Parties have caused this Agreement to be duly
executed as of the Effective Date above written.
Signature page to follow.
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CytoDyn, Inc. THE GENERAL HOSPITAL
CORPORATION
By: /s/ Xxxxx X. Xxxxx By:
------------------------- -------------------------
Name: Xxxxx X. Xxxxx Name: Xxxxx XxXxxxx
Title: President and CEO Title: Agreement Assoc.
Date: September 28, 2009 Date:
----------------------
Read and Acknowledged:
----------------------------
By: XXXX X. XXXXXXXXX, MD
Date:
Clinical Trial Agreement
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EXHIBIT A
1. PROTOCOL Protocol Summary
1.1 Rationale
In vivo studies using Cytolin, a monoclonal antibody that binds LFA1,
suggested that Cytolin increases CD4+ T cell counts and decreases HIV
viral load in HIV infected individuals. This study is a laboratory based
pilot study to determine the immunologic mechanisms of action of this
compound.
1.2. Hypothesis
Cytolin preserves CD4+ T cell number and function in vitro by inhibiting
CTL mediated killing of virus-specific CD4+ T helper cells.
1.3. Design
This is an observational study that will enroll 10 HIV- and 10 HIV+
individuals. Each subject will attend 3 study visits over a 6 month
period. Laboratory studies testing the in vitro effects of Cytolin on T
cell function and HIV replication will be done for each study visit.
2. Study Objectives
2.1. Primary objective - determine the in vitro effect of Cytolin on CD4+
and CD8+ T cell effector functions in HIV infected individuals.
2.2. Secondary objective - determine the in vitro effect of Cytolin on
HIV replication.
3. Introduction
3.1. Background
One of the characteristic features of HI V infection is the progressive
loss of CD4+ T cells. There arc likely several mechanisms by which CD4+ T
cells are lost. One possibility is that these cells are killed by
cytotoxic T lymphocytes 1. Since there are relatively few HIV infected
CD4+ T cells, if CTL lysis is a major contributor to the loss of CD4+ T
cells, then killing of both infected and uninfected CD4+ T cells would
have to occur. It has been observed that CD8+ CTL from HIV infected
individuals but not HIV seronegative controls lyse activated CD4+ T cells
1. The mechanism of lysis appears to be MHC restricted, as HLA mismatched
targets were not lysed. This means that C08+ CTL from HIV+ subjects
recognized an unknown antigen normally presented via MHC class I on
activated CD4+ T cells.
Cytolin is a murine monoclonal antibody that binds to an epitope (also
known as S6FI) on Lymphocyte Function-Associated Antigen I (LF Al )2. This
epitope is preferentially expressed on cytolytic CD8+ T cells and appears
to be induced following antigen specific activation. It is also present on
null cells (such as NK cells) and infrequently on CD4+ T cells. CD8+ T
cells expressing S6Fl have been shown to be elevated during the
asymptomatic phase of HIV infection3. Furthemwre, the CD8+ T cells that
kill HIV -infected cells are known to express the S6FI epitopc4-. Although
some anti-LFAI antibodies have been shown to block cytolysis, anti-S6Fl
antibodies do not appear to block this effector function 2.
LFAI is an adhesion molecule expressed on T cells. Binding of LFA1 to ICAM
on antigen presenting cells stabilizes the interaction between the cells
allowing signaling through the T cell receptor. ICAM is also expressed on
lymphocytes. During budding, HIV incorporates ICAM into its envelope.
Transmission of HIV into uninfected T cells is facilitated by the LFA1 -
rCAM interaction. Anti-LFA1 antibodies have been shown to inhibit
cell-to-cell transmission of HIV. It is currently unknown whether Cytolin
has this affect.
Cytolin has been tested as a therapeutic in HIV infected individuals 5, 6.
In pilot studies, Cytolin was shown to reduce HIV plasma viral load by
0.5-1 log and increase relative CD4+ T cell counts. Since viral load and
CD4+ T cell counts arc predictive of clinical progression, these results
suggest that the use of Cytolin may delay disease progression.
3.2. Rationale
This study is a laboratory based pilot study to test the hypothesis that
Cytolin preserves CD4+ T cell number and function and decreases HIV
replication in vitro. Cytolin has been administered on a compassionate use
basis to HIV infected individuals. These studies suggested that Cytolin
may increase CD4+ T cell counts and decrease HIV viral load in infected
individuals. It is hypothesized that the increase in CD4+ T cell number is
a result of
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Cytolin inhibiting lysis of uninfected CD4+ T cells by CD8+ cytotoxic T
Lymphocytes (CTL). It is currently unknown whether the increase in CD4+ T
cell number also restores CD4+ T cell effector functions which are
typically weak or absent in HIV infected individuals. The decline in viral
load observed in subjects treated with Cytolin is thought to occur as a
result of inhibiting transmission of the virus to uninfected cells by
preventing the interaction of adhesion molecules that arc incorporated
into the viral envelope with their ligands on target cells. However, this
hypothesis is based on the use of other antibodies that bind LFA1. It is
currently not known whether Cytolin has the same effect.
4. Selection and Enrollment of Subjects
4.1. Inclusion Criteria
o Men and women age 18-65 years
o HIV seropositive - subjects identified with HIV infection defined by
a positive HIV 1/2 ELISA and HIV-l Western Blot who do not meet
criteria for antiretroviral therapy (viral load<100,000 copies/ml,
CD4+>350 cells/ul).
o HIV seronegative - subjects identified as HIV uninfected defined by
a nonreactive HIV 1/2 ELISA.
o Ability and willingness to give written informed consent.
4.2. Exclusion Criteria
o Presentation with an opportunistic infection or AIDS-defining
illness.
o Receipt of investigational research agent within 30 days prior to
study entry.
o Prior receipt of experimental HIV vaccine. Individuals who received
a saline placebo are not excluded, provided they did not receive a
sham vector or adjuvant.
o Receipt of immunosuppressive medications or immune modulators within
the past six months. Individuals taking corticosteroid nasal spray
for allergic rhinitis, topical steroids or over the counter
medications for acute, uncomplicated dermatitis for a period no
longer than 14 days will not be excluded.
o Active drug or alcohol use, dependence, or psychiatric illness that
in the opinion of the study investigator would interfere with
adherence to study protocol.
o Serious illness requiring hospitalization.
4.3. Study Enrollment Procedures
This protocol and the informed consent will be reviewed and approved by
the Massachusetts General Hospital/Partners Protection of Human Subjects
Committee (MGH IRB) prior to implementation of the study. When an
individual has been identified as a potential candidate for the study,
study staff will explain the details of the study and obtain written
informed consent.
5. Study Treatment
No treatment will be given to any subject enrolled in this study. If a
subject becomes eligible for antiretroviral therapy, treatment can be
initiated at the discretion of the subject and his/her health care
provider. Subjects who initiate antiretroviral therapy may continue on the
study.
6. Clinical Evaluations
6.1. Schedule of events
Three study visits are scheduled at 3 month intervals over the course of 6
months. There will be a window period of +/- 7 days around the specific
study date in which the subject will be allowed to participate in thc
scheduled encounter. The date of all study visits will be determined at
study entry.
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Evaluation Entry 3 month 6 month
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Medical History X
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Physical Exam/medications X
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HIV ELISA and Western Blot X
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CMV, EBV, VZV serology X
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HLA typing X
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HIV RNA viral load X X X
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CD4+/CD8+ subsets X X X
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Immunology studies X X X
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Virology studies X X X
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6.2. Special Instructions and Definition of Evaluations
o A medical history must be present in source documents and completed
prior to enrollment. The medical history should include any previous
non-HIV related diagnoses of major organ systems.
o A medication history documenting any previous use of immune-based
therapies, HIV -related vaccines, antiretroviral therapies must be
obtained at study entry.
o A physical exam will be performed at study entry which includes
determination of xxxxx xxxxx (temperature, pulse, blood pressure)
and weight. Signs and symptoms of HI V-related and AIDS defining
events will be documented. All confirmed and probable diagnoses made
since the last study visit will be recorded in source documents.
o Enumeration of the absolute count and percentage of CD4+ and CD8+
lymphocytes must be done by MGH clinical laboratory which is a CLIA
certified clinical laboratory.
o Plasma HIV RNA will be performed using the Roche standard method by
the MGH clinical laboratory which is CLIA and VQA certified.
o Class I HLA typing will be done.
o The plasma titer of antibodies to Cytomegalovirus, Xxxxxxx Bar
virus, and Varicella Zoster virus will be determined.
o Laboratory studies - see section 8.
7. Laboratory Studies
7.1. Primary Objective - determine the ill vitro effect of Cytolin on T
cell number and effector functions in HIV infected individuals.
7.1.1. To determine the effect of Cytolin on T cell number, PBMC
will be incubated in the presence and absence of Cytolin and
the frequency of CD4+ and CD8+ lymphocytes will be assessed
using flow cytometry. Since Cytolin is hypothesized to prevent
the lysis of activated CD4+ T cells, the cells will
additionally be stained with CD69, CD25, and CD38 to determine
if these cellular subsets arc preferentially maintained in
cultures which contain Cytolin. It has previously been shown
that CTL from HIV+ but not HIV- subjects lyse activated CD4+ T
cells. Therefore, thcsc experiments will be done using cells
from seropositive and seronegative donors. We anticipate that
Cytolin will have no significant effect on CD4+ T cell numbers
from HIV- subjects.
7.1.2. Based on the currently available data it is unclear whether
Cytolin will block lytic activity of CTL. Furthermore, we arc
interested in whether Cytolin can block lysis of un infected
but not infected CD4+ T cells. To determine whether Cytolin
prevents lysis of target cells, infected CD4+ T cells will be
used as targets and autologous CD8+ T cells will be used as
effectors in a flow cytometry based cytotoxicity assay. In
this assay, targets are labeled with Cell Tracker Orange then
added to CD8+ effectors in the presence and absence of
CylOlin. Following incubation, target cell death is measured
by incorporation of 7AAD. Infected target cells will be
identified using an antibody to the HIV protein, p24. This
will allow us to determine the relative number of infected and
uninfected CD4+ T cells that arc lysed. We will also label
effector cells with antibodies against CDJ07a and granzymes to
correlate these effector molecules with lytic activity.
7.1.3. Although S6F1 is preferentially expressed on cytolytic CD8+ T
cells, it has also been shown to be expressed on a
subpopulation of CD4+ T cells. The effect of Cytolin on CD4+ T
cells is currently unknown. To determine whether Cytolin binds
to CD4+ T cells, an aliquot of Cytolin will be conjugated to a
fluorophore then used to label CD8+ depleted PBMC. Cells will
also be stained with the activation markers XX00, XX00, XX00
and the cytolytic marker CDI07a. This will allow us to
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determine whether activated, cytolytic CD4+ T cells bind
Cytolin. These experiments will be performed on HIV+ and HIV-
subjects to determine whether the S6Fl epitope is
differentially regulated on CD4+ cells in HIV+ individuals.
7.1.4. To determine the effect of Cytolin on CD4+ T cell functions
proliferation, cytokine secretion (IL2, TNFa, IFNg), and
expression of the co-stimulatory marker CD4+0L will be assess
in the presence and absence of Cytolin by flow cytometry. PBMC
or CD8+ depleted PBMC will be incubated with Cytolin then
stimulated with antigen (CMV, EBV, VZV, or HIV) to determine
the direct and indirect effects of Cytolin on CD4+ T cells.
Since CD4+ T cell function is typically weak or absent in HIV
infected individuals, these experiments will be performed on
HIV+ and HIV- subjects. This will allow us to determine
whether function can be restored in HIV+ subjects. Ifnot,
experiments using cells from the HIV- subjects may provide
insight into whether CD4+ T cell function is altered in any
way. If so, Cytolin may benefit HIV+ subjects who maintain
CD4+ T cell function as a result of being treated very early
during the course of their infection.
7.2. Secondary objective - determine the in vitro effect of Cytolin on
HIV replication.
7.2.1. Transmission of HI V from cell-to-cell is facilitated by
interactions between LFA1 and ICAM. Given that Cytolin reduced
viral loads in HIV infected individuals, we hypothesize that
Cytolin blocks this interaction. To test this hypothesis HIV
infected PHA blasts will be co-cultured with uninfected target
cells in the presence and absence of Cytolin and viral
replication will be determined using a p24 assay. These
experiments will be performed using cells from HIV- subjects.
7.2.2. An alternative hypothesis is that infected cells are lysed
even the presence of Cytolin. Although this hypothesis is
being addressed as described in section 8.1.2, we will further
test this hypothesis by measuring the ability of CTL to
suppress HIV replication in the presence and absence of
Cytolin. In this assay, HIV infected CD4+ T cells are
co-cultured with autologous CD8+ T cells and viral replication
is monitored using a p24 ELISA. These experiments take into
account all CD8+ T cell effector functions, not just cell
killing. This approach may provide additional insight into the
mechanisms of action of Cytolin in vivo. These experiments
will be performed using cells from HIV+ and HIV - subjects.
8. Statistical Considerations
8.1. General Design Issues
The design of this study reflects the need to obtain blood from HIV+ and
HIV- individuals in order to determine the in vitro effect of Cytolin on T
cell function and HIV replication.
8.2. Sample Size Considerations
Our experience with these type of experiments suggests that 10 HIV+ and JO
HIV- subjects will be sufficient to extract meaningful results.
8.3. Enrollment and Accrual
Based on the history of recruitment of subjects with HIV infection at the
study site, it is anticipated that one to four subjects per month may be
recruited. Thus it is expected that it will take one year to enroll all
subjects.
Experience at this site indicates that patients will likely show good
adherence to the study visit schedule.
8.4. Monitoring
Data completeness and quality will be monitored monthly by the laboratory
manager and the study manager. Because of the small size and single site
nature of the study it will be easy to examine the data for
inconsistencies and missing data. Data will also be assessed for
completeness and accuracy and inconstancies will be addressed with each
research subject at the final study visit.
9. Data Collection and Monitoring
9.1. Records to be kept
At enrollment written informed consent will be obtained by study staff and
recorded in the research chart. At each study visit, all clinical data
including demographic data, HIV viral load, and T cell counts will be
collected
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using standardized forms created in advance specifically for this study.
Data from these forms will be entered into a database within two weeks of
the study visit. At study entry, retrospective HIV viral load, CD4+ and
C08+ counts will be obtained from the subjects primary care physician if
it is available.
Subjects will not be identified by name on any forms, but rather by a
patient identification number (PID) assigned by study staff at enrollment.
The key to the identity of subjects will be maintained solely by the Study
Coordinator.
Research charts will be kept on site in a locked cabinet or room during
the entire study period, which will end two months after the final study
visit of the last enrolled subject. The study database will be password
protected and only available to study staff.
9.2. Role of Data Management
Xxxx X. Xxxxxxxxx, MD, principal investigator, is responsible for the
Clinical Management Plan for this protocol at Massachusetts General
Hospital.
Xxx Xxxxxx, MSN NP, Study Coordinator, has been designated by Xx.
Xxxxxxxxx to be responsible for the implementation of the Clinical Quality
Management Plan.
Xxxxx Xxxxxxx, PhD, Laboratory Coordinator, has been designated by Xx.
Xxxxxxxxx to be responsible for the implementation of the Laboratory
studies.
9.3. Clinical Site Monitoring and Record Availability
This is a single site study and all monitoring will be conducted at the
Massachusetts General Hospital. All study records will be kept in a locked
cabinet.
10. Human Subjects
10.1 Institutional Review Board (IRB) review and Informed Consent
This protocol and the informed consent document and any subsequent
modifications will be reviewed and approved by the IRT or ethics committee
responsible for oversight of the study. A signed consent form will be
obtained from the subject. The consent fonn will describe the purpose of
the study, the procedures to be followed, and the risks and benefits of
participation. A copy of the signed consent will be given to the subject
and documented in the research chart.
10.2. Subject Confidentiality
All laboratory specimens, evaluation forms, reports, and other records
will be identified with the PID to maintain subject confidentiality. All
records will be kept locked. All computer and networking programs will be
done with coded numbers only. Clinical information will not be released
without written permission of the subject, except when necessary for
monitoring by IRB or the Office for Human Research Protections.
10.3. Study Discontinuation
The study may be discontinued at any time by the IRB or other government
agencies as part of their duties to ensure the protection of research
subjects.
11. Biohazard Containment
Appropriate precautions to prevent the transmission of HIV and other blood-borne
pathogens will be undertaken in the drawing of blood, shipping and handling of
specimens, and all laboratory experiments.
12. References
1. Xxxxxxx 1M, Xxxxxxxxx XX, Xxxx J, et a1. HIV-infected humans, but not
chimpanzees, have circulating cytotoxic T lymphocytes that lyse uninfected
CD4+ cells. J Immunol. Apr 15 1990;144(8):2992-2998.
2. Morimoto X. Xxxx CE, Xxxxxx XX, Xxxxxxxxxx XX. A novel epitope of the
LFA-I antigen which can distinguish killer effector and suppressor cells
in human CDS cells. Nature. Dee 3-9 1987;330(6147):479482.
3. Xxxxxxxx F, Traldi A, Xxxxxxxx R. Phenotypical and functional evaluation
of CD8+/S6F 1+ T lymphocytes in haemophiliac individuals with HIV-I
infection. Clin Exp Immunol. Jul 1993;93(1):51-55.
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4. Tsubota H, Lord CI, Xxxxxxx Dr, Xxxxxxxx C, Xxxxxx XX. A cytotoxic T
lymphocyte inhibits acquired immunodeficiency syndrome virus replication
in peripheral blood lymphocytes. J Exp Med. Apr 1 1989; 169(4): 1421-1434.
5. Xxxxx AD, Xxxx XX, Xxxxxxxxx XX, Xxxxxxxx MI, Xxxxxxx XX, 2nd, Vidikan P.
Leukocyte adhesion molecules as a cofactor in AIDS: basic science and
pilot study. Med Hypotheses. Aug 1995;45(2): 164-168.
6. Xxxxx AD, Xxxxxx T, Vidikan P, Beer V. Pitfalls in the use of surrogate
markers for human immunodeficiency virus disease: further evidence on
pathogenesis. Med Hypotheses. Jul 1996;47(1):27-30.
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EXHIBIT B
BUDGET AND PAYMENT SCHEDULE
Clinical Trial Agreement
