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Exhibit 10.12.3    
    

AMENDEMENT No. 2 TO CLINICAL TRIAL AGREEMENT  

        This AMENDMENT NO. 2 TO CLINICAL TRIAL AGREEMENT (the "Amendment 2") is made and entered into as of the 28th day of January, 2004, by and between  Gentium
S.p.A. (formerly Crinos Industria Farmacobiologica S.p.A.) a corporation having an office at Piazza XX Settembre 2, 22079 Villa Guradia, Como
Italy (the "Company") and Dana-Farber/Partners Cancer Care, Inc., a non-profit corporation having an office at 44 Binney Street,
Boston, Massachusetts, 02115, USA ("DFPCC"). 

        WHEREAS,
the Company and DFPCC entered into a Clinical Trial Agreement dated December 27, 1999 (the "Clinical Trial Agreement") and an Amendment No. 1 to Clinical Agreement
in October 2000 (the "Amendment"), which relates to the conduct of a clinical study of Defibrotide in accordance with the study protocol entitled "Defibrotide for Hematopoietic Stem Cell
Transplant (SCT) Patients with Severe Hepatic Veno-Occlusive Disease (VOD): A Randomized Phase I/II Study to Determine the Effective Dose;" and 

        WHEREAS,
the parties desire to expand the number of subjects participating in the Study. 

        NOW,
THEREFORE, in consideration of the mutual agreements, promises and covenants provided herein, the Company and DFPCC hereby agree to amend the Clinical Trial Agreement as follows: 

Section 1: Budget  

        With reference to Section 4: Budget of the Clinical Trial Agreement, this section is hereby amended to
include an additional Two hundred thousand U.S. Dollars ($200,000) and restated in its entirety to read as follows: 

Company
agrees to support this Study with a research grant of Four hundred fifty thousand U.S. Dollars ($450,000) inclusive of indirect costs. The agreed upon budget is attached hereto as
Exhibit B. 

        IN
WITNESS WHEREOF, THE COMPANY AND DFPCC have by their own hands or by their respective officers executed the Amendment No. 2 to Clinical Trial Agreement effective as of the date
first set forth above. 

	THE COMPANY:

CRINOS INDUSTRIA

FARMACOBIOLOGICA S.P.A.	 	DFPCC:

DANA-FARBER/PARTNERS CANCER

CARE, INC.
	

GENTIUM S.P.A.	
 	

 	

 
	

BY:	

/s/  Laura Iris Ferro      
	
 	

BY:	

/s/  Willam M. Corbett, Jr.      

	

TITLE:	

PRESIDENT
	
 	

TITLE:	

WILLIAM M. CORBETT, JR.

DIRECTOR OF RESEARCH ADMINISTRATION

	

DATE:	

March 19, 2004
	
 	

DATE:	

2/9/04

	

 	

 	
 	

 	

 

        I
have read the foregoing Amendment No. 2 and agree to comply with the obligations of Investigators stated therein. 

	

/s/  Paul Richardson      
 Paul Richardson, M.D.	
 	

 
	

 	
 	

 	
 	

 
	

DATE:	
 	

    
	
 	

 

        "Diferotide
for Hematopoietic Stem Cell Transplant (STC) Patients with Severe Hepatic Veno-Occlusive Disease

(VOA): A Phase I/II Study to Determine Minimal Effective Dose" 

	Protocol No

Duration of Study (months)

Number of Patients
	 	99-118

12

20

(total of 80pts)
	 	Company Name

Overall Site

Overall P.I.

Site P.I.
	 	CRINOS

DFCI

RICHARDSON, MD

	BUDGET ITEMS
	 	Percent Effort
	 	Study Total
	 	Amount Per Patient

	PERSONNEL:	 	 	 	 	 	 	 	 
	Site Principal Investigator	 	11%	 	$	16,512	 	$	826
	Project Manager	 	45%	 	$	25,775	 	$	1,289
	Data Manager (Parisa Momtaz)	 	100%	 	$	38,272	 	$	1,914
	Research Nurse	 	0%	 	$	0	 	$	0
	 	 	
	 	
	 	

	 	Total Salaries	 	 	 	$	80,559	 	$	4,028
	Employee Benefits    M.D.	 	29.00%	 	$	4,789	 	$	239
	Employee Benefits    Non-M.D.	 	26.00%	 	$	16,652	 	$	833
	 	 	
	 	
	 	

	 	Total Benefits	 	 	 	$	21,441	 	$	1,072
	 	 	
	 	
	 	

	TOTAL PERSONNEL	 	 	 	$	102,000	 	$	5,100
	 	 	
	 	
	 	

	
OUTPATIENT CARE COSTS	
 	

 	
 	
 	

 	
 	
 	

 
	Tests/Procedures, etc.	 	 	 	$	0	 	$	0
	 	Subtotal Outpatient Care	 	 	 	$	0	 	$	0
	INPATIENT CARE COSTS	 	 	 	 	 	 	 	 
	Bed Day Rates	 	None	 	 	 	 	 	 
	Other Procedures	 	 	 	$	0	 	$	0
	 	Subtotal Inpatient Care	 	 	 	$	0	 	$	0
	
PHARMACY: Prep, Storage, etc.	
 	

Pharmacy Charge Form	
 	
$	

0	
 	
$	

0
	 	 	
	 	
	 	

	TOTAL PATIENT CARE	 	 	 	$	0	 	$	0
	 	 	
	 	
	 	

	Pharmacokinetics	 	DFCI/MGH/Other

ý  ý  ý	 	$	50,000	 	$	2,500
	 	 	
	 	
	 	

	TOTAL PHARMACOKINETICS*	 	 	 	$	50,000	 	$	2,500
	 	 	
	 	
	 	

	*Includes set-up charge of $15,000 at Childrens Hospital
	
OTHER EXPENSES	
 	

 	
 	
 	

 	
 	
 	

 
	Supplies	 	 	 	$	1,000	 	$	50
	Shipping Costs	 	 	 	$	0	 	$	0
	Travel (Protocol or Scient. Mtgs)	 	 	 	$	2,500	 	$	125
	Equipment	 	 	 	$	0	 	$	0
	Shared Resources (eg, MDLab)	 	 	 	$	0	 	$	0
	Storage Fees	 	 	 	$	0	 	$	0
	CER Lab	 	 	 	$	4,500	 	$	225
	 	 	
	 	
	 	

	TOTAL OTHER EXPENSES	 	 	 	$	8,000	 	$	400
	 	 	
	 	
	 	

	TOTAL DIRECT COSTS:	 	 	 	$	160,000	 	$	8,000
	 	 	
	 	
	 	

	Indirect Costs @ 25% Total Direct Costs	 	 	 	$	40,000	 	$	2,000
	 	 	
	 	
	 	

	TOTAL COSTS PER PATIENT**	 	 	 	$	200,000	 	$	10,000
	 	 	
	 	
	 	

	
Protocol Review and Renewals	
 	

 	
 	
$	

0	
 	
 	

 
	 	 	
	 	
	 	

	Start-Up Costs	 	 	 	$	0	 	 	 
	 	 	
	 	
	 	

	TOTAL STUDY COSTS**	 	 	 	$	200,000	 	 	 
	 	 	
	 	
	 	

**Includes
payments to sub-contract sites 

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Exhibit 10.13    
    

Trial Agreement  

 involving  

 Gentium S.p.A.  

 and the  

 EBMT  

 
CONTENTS OF SECTIONS  

	 
	 	 

	1. Conduct of the Study	 	2
	

2. Responsibilities	
 	

2
	

3. Liability and Indemnity	
 	

3
	

4. Financial Support	
 	

3
	

5. Confidentiality, Publication and Data Access	
 	

4
	

6. Terms and Termination	
 	

4
	

7. General Provision	
 	

4

Attachments:            Appendix 1            Final
Protocol (dated 11 February 2004) 

 THIS AGREEMENT is made the 26th day of February, 2004 by and between: 

	1.
	Gentium
S.p.A. (hereinafter referred to as Gentium), Piazza XX Settembre, 2 D-22079 Villa Guardia (CO), Italy

	2.
	European
Group for Blood and Marrow Transplantation (hereinafter referred to as EBMT), Macdonald Buchanan Building, John Astor House, Foley Street, London W1P 8AN, UK England; and
represented by Selim Corbacioglu, Principal Investigator, and Jane Apperley, President of EBMT 

WHEREAS:  

	(A)
	Gentium
is interested in the use of Defibrotide in the prophylaxis of venoocclusive disease (VOD).

	(B)
	The
EBMT wishes to undertake a clinical trial involving Defibrotide to investigate and evaluate the use of Defibrotide for the prophylaxis of venoocclusive disease (VOD) in a high
risk pediatric population after stem cell transplantation

	(C)
	The
said trial is to be conducted pursuant to a protocol entitled: 

"VOD-DF Study

Prospective Study of the Incidence and Outcome of Veno-occlusive Disease (VOD) with the Prophylactic Use of Defibrotide (DF, Gentium, Italy) in Pediatric Stem
Cell Transplantation"

1

 

IT IS HEREBY AGREED THAT:  

 
 
	1
	 CONDUCT OF THE STUDY

	1.1
	The
EBMT shall undertake the study providing several elements as depicted in '2. Responsibilities' (see below) like insurance coverage
for participants randomised in the above mentioned international project as set down in the protocol

	1.2
	The
study shall be conducted under the co-sponsorship of the EBMT

	1.2.1
	in
all EBMT participating centres selected by the EBMT and agreed by Gentium

	1.2.2
	in
accordance with the Protocol and any amendments to the Protocol as approved by all parties

	1.2.3
	with
patients selected in accordance with the criteria specified in the Protocol

	1.2.4
	only
after all necessary legal or other approvals have been granted including without limitation those of the Data Monitoring committee or any ethics committee at the Participating
Centres and strictly in accordance with the terms of any such approval

	1.2.5
	in
accordance with the principles of the standards of good clinical practice
 
   

 
	2
	 RESPONSIBILITIES

	2.1
	Obligations
of the EBMT

	2.1.1
	Insurance
coverage for each patient of the study for each participating centre.

	2.1.2
	Online
data management which will include: Maintenance of hardware (servers) and software, education of participants in software use, management of password, username and TAN
(transaction numbers) distribution and maintenance, cleaning for data consistency, timely followup on data collection based on enrolment figures and all statistical analyses as described in the
protocol.

	2.1.3
	With
the strict prerequisite that the 'Deutsche Krebshilfe' will grant financial support, the EBMT will provide a study co-ordinator; provide the server necessary for
the online data management and organize the monitoring of participating centers in Germany.

	2.1.4
	The
EBMT will require Clinical Investigators and Participating Centres to treat any information provided to them by Gentium in accordance with terms equivalent to the
confidentiality provisions of Article 5 of this Agreement.

	2.1.5
	The
management of the Study at each Participating EBMT Centre.

	2.1.6
	EBMT
data management centre will notify Gentium, Villa Guardia within 24 hours of any Serious Adverse Event. Contact details in Appendix 1.

	2.1.7
	EBMT
data management centre will provide Gentium with information of the progress of the trial, such information is to be provided on a quarterly basis in writing (electronic or by
regular mail). Reports will include progress of the study, countries involved, name of the centre, name of the investigator, number of patients enrolled with date of randomisation, eligibility status,
treatment status and last follow-up date.

	2.1.8
	EBMT
will provide Gentium with a copy of the final study report within a reasonable time but not exceeding eight months after the last patient has discontinued therapy. Data on
adverse events will be provided upon request to enable Gentium to meet legal obligations to any regulatory authority. Upon request the Analysis database will be provided in the existing format to
Gentium. 

2

 
	2.2
	Gentium:

	2.2.1
	Will
provide assistance to the EBMT until December 2008 (see Clause 4.1) in order that the EBMT may undertake the Study and discharge its obligations and
responsibilities as set out in Clause 2.1.

	2.2.2
	Agrees
to provide clinical trial drug for eligible participants. In detail Gentium will arrange for packaging, labeling, coding, supplying and handling of the investigational
product.

	2.2.3
	Will
conduct the monitoring of the international (non-German) participating centres according to ICH/GCP-criteria and the internal standards laid out in the
monitoring handbook used for Germany.

	2.2.4
	Will
handle IEC/IRB board submissions and will comply with national and local health regulations and requirements in order to conduct the study according to the national law in
participating countries.

	2.2.5
	Will
provide SAS-based back-up data management according to ICH/GCP-criteria. Obligations will include data entry into a central database and cleaning for
data consistency in agreement with the online-based data management of the EBMT.

	2.2.6
	Will
conduct investigator meetings according to the requirements of the
 
   

 
	3
	 LIABILIY AND INDEMNITY

	

	The
EBMT will be deemed co-sponsor of the Study. The EBMT will take out a clinical trial insurance policy to provide compensation to
participants in the study suffering injury or death caused by the administration of Defibrotide.
 
   

 
	4
	 FINANCIAL SUPPORT

	4.1.1
	Annual
budget table 

	Annual Budget (in Euro)
 
	 	Year 1
	 	Year 2
	 	Year 3
	 	Year 4
	 	Year 5
	 	Total
	 
	Study co-ordinator	 	56.000,00	 	56.000,00	 	56.000,00	 	56.000,00	 	—	 	224.000,00	 
	Non-recurrent costs	 	5.000,00	 	 	 	 	 	 	 	 	 	5.000,00	 
	Monitoring

(approximation)	 	26.000,00	 	26.000,00	 	26.000,00	 	26.000,00	 	—	 	104.000,00	 
	Travel expenses	 	11.000,00	 	11.000,00	 	11.000,00	 	11.000,00	 	5.500,00	 	49.500,00	 
	Communication

(approximation)	 	1.200,00	 	1.200,00	 	1.200,00	 	1.200,00	 	1.200,00	 	6.000,00	 
	IEC/IRB, health authorities

(approximation)	 	5.000,00	 	5.000,00	 	5.000,00	 	—	 	—	 	15.000,00	 
	Investigator meetings

(approximation)	 	10.000.00	 	10.000.00	 	(10.000.00	)	—	 	—	 	20.000,00

(30.000,00	
)
	Trial insurance policy

(approximation)	 	10.575,00	 	10.575,00	 	10.575,00	 	10.575,00	 	 	 	42.300,00	 

	4.1.2
	Early
termination of the study (e.g. data monitoring committee decision based on interim analysis) or failure to recruit the planned number of patients according to protocol
(100-150 patients per year), will end this contract with a pro-rata payment based on enrolled eligible patients.

	4.2
	Study
data and all copyrights created in connection with the execution of this agreement shall be joint property of Gentium and EBMT. Any invention or discovery, whether patentable or
not, arising from the Study relating specifically to Gentium shall be the exclusive property of Gentium. All parties will take the steps necessary to give effect to this provision.
 
 

3

 
	5
	 CONFIDENTIALITY, PUBLICATION AND DATA ACCESS

	5.1
	This
agreement and the terms and conditions hereof shall be confidential and none of the parties shall, without the prior written permission of the disclosing party, disclose the same
to any third party except to the extent this may be

	5.2
	The
first publication of the Main Report of the results of the Study will be in accordance with the protocol and will require the approval of Gentiurn, The EBMT may wish to publish or
present scientific papers dealing with the Study in accordance with accepted scientific practice. The EBMT agrees that prior to submission of publication or any other dissemination of results
including oral dissemination the EBMT shall seek the approval of Gentium. Gentium will have a review time of 4 weeks for publication and 2 weeks for posters and presentations.

	

	Authorship
of the publication and presentation will follow the EBMT rules/statute

	5.3
	The
EBMT will make available the analysis database in the existing format to Gentium after completion of the Study as provided in Clause 2.1.8 hereto for the purposes of safety
analysis.
 
 

	6
	TERMS AND TERMINATION

	6.1
	This
agreement shall enter into full force and effect retrospectively on the 1st of February 2004 and shall continue until the Study is complete upon publication
by the EBMT of the Main Report or as otherwise terminated as provided for herein.

	6.2
	Any
party may terminate this financial agreement forthwith by notice in writing to the other if the other party commits a breach of this agreement which in the case of a breach
capable of remedy shall not have been remedied within sixty (60) days of the receipt to the party in default of a notice identifying the breach and requiring its remedy. It is expected that
such notice to terminate this agreement will not be issue until the matter in question has been raised and discussed during the 60-day period.

	6.3
	The
EBMT or Gentium shall after having discussed this with the other party, be entitled to terminate the Study in whole or in part in the following circumstances:

	6.3.1
	Forthwith
following a review of the data and other know-how generated in the study that demonstrates the results generated may be of negligible scientific value

	6.3.2
	Forthwith
on the advice of the Data Monitoring Committee and /or Ethical Committee on the grounds that

	(i)
	the
safety of the patients in the Study warrants termination of the whole or part of the Study or

	(ii)
	no
significant difference is likely to be demonstrated between the various regimes.
 
 

 

	7
	GENERAL PROVISIONS

	7.1
	Gentium
and the EBMT have no obligation to renew this agreement. Gentium is not under any obligation to enter into another type of agreement with the EBMT at this time or in the
future.

	7.2
	Each
Gentium and the EBMT warrants and represents to the other that both have the full right and authority to enter into another type of agreement and that both are not aware of any
impediment which would inhibit their ability to perform their obligations hereunder. 

4

 
	7.3
	GOVERNING
LAW AND JURISDICTION

	

	The
validity, construction and performance of this agreement will be governed by and construed for all purposes in accordance with the law of Italy and the
jurisdiction lies in the courts of Milan, Italy. 

	For and on behalf of Gentium:	 	For and on behalf of Gentium:
	

/s/  MASSIMO IACOBELLI      
	
 	

/s/  LAURA IRIS FERRO      

	Name:	 	Massimo Iacobelli	 	Name:	 	LAURA IRIS FERRO
	Title:	 	Medical Director	 	Title:	 	PRESIDENT
	Date:	 	20.05.04	 	Date:	 	20.05.04
	

For and on behalf of the EBMT:	
 	

For and on behalf of the EBMT:
	

/s/  SELIM CORBACIOGLU      
	
 	

/s/  JANE F. APPERLEY      

	Name:	 	Dr. Selim Corbacioglu	 	Name:	 	Prof. Jane Apperley
	Title:	 	Principal Investigator	 	Title:	 	President of the EBMT
	Date:	 	20th March 2004	 	Date:	 	10th March 2004

5

 
Appendix A  

 Protocol  

[Intentionally
Deleted.] 

6

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Exhibit 10.13

1. Conduct of the Study

2. Responsibilities

3. Liability and Indemnity

4. Financial Support

5. Confidentiality, Publication and Data Access

6. Terms and Termination

7. General Provision

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