This protocol amendment is designed for the introduction of a new batch of BT088 in the trial due to the expiry of the current study medication. In the production process of the respective batch an additional filtration step through a 20 nm virus filter was implemented. All plasma derived products manufactured by Biotest are virus safe as demonstrated by virus validation studies and clinical experience. As a result of demonstrated viral safety according to the Note for Guidance “Virus Validation Studies (Revised) (CPMP/BWP/268/95) Biotest products (e.g. Intratect, Hepatect CP) are licensed by regulatory authorities world wide. The requirements on virus removal/inactivation are different in EU countries. Some regulatory authorities thus require an additional step for virus inactivation or virus removal especially for non enveloped viruses. For the European harmonisation of viral safety requirements Biotest will establish an additional step of virus removal by 20 nm virus filtration. This step further improves the margin of safety of our products. The modified manufacturing scheme and the pharmaceutical properties of BT088 are displayed in section 4 of the Amendment No. 1 to the Investigator's Brochure. SA dated 20April2007 has been integrated in the protocol version 3.0 dated 02 January 2007.

This protocol amendment is designed for subsequent extension of the expiry date of the current batch. Extension of expiry date of the current batch (A098027) Stability tests for BT088 were performed and the stability indicating parameters which were assessed admit an extension of the expiry date until August 2008. The study medication will be labelled according to § 5 (in particular paragraph 7) GCP-Ordinance (GCP-Verordnung). An (additional) label will be affixed on the blister and to the outer packaging presenting the new expiry date and the batch identification number, respectively. Formal adaptations to the study protocol are not applicable for extension of the expiry date as an (additional) label will be provided according to the GCP-Ordinance presenting the following data: Batch number: A098027A; Expiry date: 31.08.2008 SA dated 19Dec2007 has been integrated in the protocol version 3.0 dated 02 January 2007.

Replacement of the current study medication which expires in August 2008 (Batch number: A098027A). This protocol amendment is designed for the introduction of a second nanofiltered batch of BT 088 (Batch number: A098047 - Expiry date: 31.05.2009) as replacement of the current study medication which expires in August 2008 (Batch number: A098027A). The study medication will be labelled according to § 5 (in particular §7) GCP-Ordinance (GCP-Verordnung). The alterations referring to the Substantial Amendment No 2, dated 19th December 2007, page 5 of 5, “Formal Aspects of the Amendment_Batch No.: A098027A; Expiry date: 31.08.2008”. SA dated 05Mar2008 has been integrated in the protocol version 3.0 dated 02 January 2007.

This protocol amendment is designed for the introduction of a subsequent version 3 of Investigational Medicinal Product Dossier (IMPD) and the respective Investigator's Brochure (IB) Version 3. The scope of changes comprses an update of the stability data of the drug substance and drug product and a change of material of syinge tip cap (rubber composition). Furthermore, planned study dates in the study protocol and in the patient informed concent had to be actulised due to slow recruitment rates. This amendment refers to the batch number A=)(=$/ with expiry date 31.05.2009 (Substantial Amendment, dated 5th March 2008).

Only for Hungary : This protocol amendment is designed for the introduction of a central laboratory in Hungary for the determination of serology parameters in Hungarian subjects - determinations for hep. serology (HU subjects) will be performed at InterLab GmbH (central lab.). Furthermore, administrative changes are implemented - contact details of Biotest Drug Safety Department were changed. The trial conduct is not affected by the updated IMPD and IB. SA dated 27Nov2008 has been integrated in the protocol version 3.0 dated 02 January 2007.

Only for Germany - Inclusion of additional investigative sites in Germany SA dated 26Feb2009 has been integrated in the protocol version 3.0 dated 02 January 2007.

Shelf life extension of BT088 untill 30.11.2009. Change of trial coordinating investigator. SA dated 24April2009 has been integrated in the protocol version 3.0 dated 02 January 2007.

Shelf live extension to 31.10.2010. SA dated 17 September 2009 has been integrated in the protocol version 4.0 dated 21 April 2009.

The present study protocol amendment is prepared to implement a new statistical approach in terms of the study-specific patient sample size and the previously planned confirmatory analysis. Furthermore, a change of the planned dates concerning termination is necessary. In December 2008, the reasons for the change in sample size and statistical approach were presented to the German competent authority Paul-Ehrlich-Institut(PEI). Recruitment in Germany was hampered by the following difficulties: Many mothers have foreign nationalities and fathers tend to withdraw already given informed consent. Mothers do not want to stay in the hospital for three days. The collaboration between gynaecologists and paediatricians in the study centres has not always been satisfactory. There are not many children eligible for the study due to a particular patient population. Considering the recruitment rate in December 2008 and the required number of patients, even with the inclusion of Hungarian centres, the study would have required at least another two years of recruitment. Hence, it could not be granted if the study would be finalised at all under these conditions. Due to a prolonged regulatory procedure, approval in Hungary was finally received on 17.02.2009, and enrolment started not until 16.09.2009. Biotest proposed to finalise the clinical trial with a smaller sample size(n=25)to achieve a national marketing authorisation in Germany, and suggested a non-confirmatory statistical analysis. The studies used as supportive data have also been analysed with non-confirmatory statistical analyses so far. The PEI emphasized that a patient number of 25 is not optimal, but would be acceptable if data of the other clinical studies on BT088, especially study 956 and 952, will be considered. The PEI agreed that study 959 will be continued until 25 patients have been enrolled, then the study is allowed to be stopped and analysed. SA dated 17Mar2010 integrated into protocol V.4.0,21.04.2009.