Test Case # 1 - Clinical Trial (Initial Report)

Date of notification: 28-Feb-2010 Dear All, Please be informed the following information has been received for the TRE 123 Phase II, Open-Label, Non-randomized, Dose Finding Safety, Tolerance, Pharmacokinetic and Efficacy Study of Orally Administered TRE 123 versus Placebo in Patients with Hypertension. The details are as follows: Protocol Patient Event Onset Date TRE 123 ATJ / 056 Bilateral DVT 23-Feb-2010

Reporter Information: Investigator Name: Robert Hansen, MD Address: Hugenottenallee 167 City: Neu Isenburg Tel: 49 6102 296 0 State: ---Institution: Neu Isenburg University Postal/Zip code: 63263 Fax: 49 6102 397 0 Country: Germany

NOT A CRF *** NOT A CRF *** NOT A CRF *** NOT A CRF TRE 123 Protocol Site/Country: 012/Germany Patient Initials/Number: ATJ / 056 Serious Adverse Event 1.* Date of birth Gender Weight Height Serious Adverse Event Reports 2.* Report type 14 Jul 1933

Visit: SAE Page 1/2

Male Female
98 kg 182 cm

Initial report Follow-up report

Follow-up report # Date of follow-up:

3.* 4.* 5* 6.* 7.*

Did SAE occur after initiation of study drug? Event Term (diagnosis) Date event became serious Date event resolved/stabilized/improved Event outcome

Yes No
Bilateral DVT 23 Feb 2010 __ ____ ____
Recovered/resolved without sequelae Recovered/resolved with sequelae Continuing Fatal

8.*

Serious criteria Check all serious criteria that apply

9.* 10.* 11.*

Is this event possibly related to study drug? Is this event possibly related to study procedure? Are there any relevant medical history conditions not previously recorded as

Death Life-threatening at the time of the event Hospitalization Required hospitalization Date of admission: 23Feb2010 Date of discharge: 04 Apr2010 Prolongation of existing hospitalization Disability Congenital anomaly Other Yes, explanation of opinion: No Yes No Yes No

medical history conditions or pre-existing conditions? If yes, list condition and dates Relevant Medical History

12.* 13.*

Study drug start date Action taken with investigational product(s) as result of SAE

Bacterial Endocarditis Sept-1999-Oct1999, Paroxysmal Supraventricular Tachycardia Sep-1999-Sept-1999, Hypertension 08 Jan 2010

14.* 15.*

Date study drug last taken (prior to SAE) If study drug stopped and restarted, did the event reappear?

None Dose permanently discontinued Dose interrupted Not applicable 22 Feb 2010

Yes No Unknown Not applicable

Clinically Significant Tests and Diagnostic Procedures

16.*

Laboratory Test/Procedure Name Doppler ultrasound of lower extremities

D-DIMER PTT

Date and Time

Result

Units

Normal Limits

23-Sep-2010

DVT

23-Sep-2010 25-Sep-2010 06:00 General Narrative Comments 17 Provide a brief narrative description of SAE

275 70

ng/ml sec

0-240 ng/mL 18-28

Patient complained of bilateral edema in his feet and was confirmed to have bilateral DVT by lower extremity Doppler. He was admitted for management of this on 23Feb-2010. The patient had noticed the swelling for approximately 5 days before notifying the physician. The patient was treated with heparin IV and Coumadin.

Concomitant Medications 18 Amlodipine 16-Aug-2009, ongoing Hydrochlorothiazide 16-Aug-2009, ongoing Furosemide 16-Aug-2009, ongoing

Test Case # 1 - Clinical Trial (Follow-Up Report)

Date of notification: 24-Apr-2010 Dear All, Please be informed the following information has been received for the TRE 123 Phase II, Open-Label, Non-randomized, Dose Finding Safety, Tolerance, Pharmacokinetic and Efficacy Study of Orally Administered TRE 123 versus Placebo in Patients with Hypertension. The details are as follows: Protocol Patient Event Onset Date TRE 123 ATJ / 056 Bilateral DVT 23-Feb-2010

Reporter Information: Investigator Name: Robert Hansen, MD Address: Hugenottenallee 167 City: Neu Isenburg Tel: 49 6102 296 0 State: ---Institution: Neu Isenburg University Postal/Zip code: 63263 Fax: 49 6102 397 0 Country: Germany

NOT A CRF *** NOT A CRF *** NOT A CRF *** NOT A CRF TRE 123 Protocol Site/Country: 012/Germany Patient Initials/Number: ATJ / 056 Serious Adverse Event 1.* Date of birth Gender Weight Height Serious Adverse Event Reports 2.* Report type 14 Jul 1933

Visit: SAE Page 1/2

Male Female
98 kg 182 cm

Initial report Follow-up report

Follow-up report # Date of follow-up:

3.* 4.* 5* 6.* 7.* 8.*

Did SAE occur after initiation of study drug? Event Term (diagnosis) Date event became serious Date event resolved/stabilized/improved Event outcome Serious criteria Check all serious criteria that apply

Yes No
Bilateral DVT 23 Feb 2010 04 Apr 2010 Recovered/Resolved Death Life-threatening at the time of the event Hospitalization Required hospitalization Date of admission: 23Feb2010 Date of discharge: 04 Apr2010 Prolongation of existing hospitalization Disability Congenital anomaly Other Yes, explanation of opinion: No

9.* 10.* 11.*

Is this event possibly related to study drug? Is this event possibly related to study procedure? Are there any relevant medical history conditions not previously recorded as medical history conditions or pre-existing conditions? If yes, list condition and dates

Yes No Yes No

Relevant Medical History

12.* 13.*

Study drug start date Action taken with investigational product(s) as result of SAE

Bacterial Endocarditis Sept-1999-Oct1999, Paroxysmal Supraventricular Tachycardia Sep-1999-Sept-1999, Hypertension 08 Jan 2010

14.* 15.*

Date study drug last taken (prior to SAE) If study drug stopped and restarted, did the event reappear?

None Dose permanently discontinued Dose interrupted Not applicable 22 Feb 2010

Yes No Unknown Not applicable

Clinically Significant Tests and Diagnostic Procedures 12- Lead Electrocardiogram (EKG) 23-Feb-2010, 11:02 AM Results: Paroxysmal Supraventricular Tachycardia, ventricular rate 180 beats per minute, 12-Lead EKG 23-Feb2010 11:30 AM Sinus Tachycardia 104 beats per minute Laboratory Test/Procedure Name Doppler ultrasound of lower extremities
D-DIMER PTT

Date and Time

Result

Units

Normal Limits

16.*

23-Sep-2010

DVT

23-Sep-2010 25-Sep-2010 06:00

275 70

ng/ml sec

0-240 ng/mL 18-28

General Narrative Comments 17 Provide a brief narrative description of SAE Patient complained of bilateral edema in his feet and was confirmed to have bilateral DVT by lower extremity Doppler. He was admitted for management of this on 23Feb-2010. The patient had noticed the swelling for approximately 5 days before notifying the physician. The patient was treated with heparin IV and Coumadin.

Concomitant Medications 18 Amlodipine 16-Aug-2009, ongoing Hydrochlorothiazide 16-Aug-2009, ongoing Furosemide 16-Aug-2009, ongoing

Test Case # 2 - Clinical Trial (Initial Report)

Date of notification: 18-Mar-2010 Dear All, Please be informed the following information has been received for the TRE 123 Phase III, Double-blind, Randomized Safety, Pharmacokinetic and Efficacy Study of TRE 123 versus Placebo in Patients with Coronary Artery Disease. The details are as follows: Protocol Patient Event Onset Date TRE 123 045 / ADF Congestive Heart Failure 16-Mar-2010

Reporter Information: Investigator Name: Olivia Stone, MD Address: 4566 Hudson Lane City: Hollywood State: CA Institution: Hollywood Research Institute Postal/Zip code: 90068 Country: United States

Tel: 818-555-1234 Fax: 818-555-6789

Subject: 045 - ADF Page: Adverse Event/Serious Adverse Event Adverse Event (1)

Term

Onset date

Relation

Involved/ hospitalization

Prolonged hospitalization

Death

Lifethreatening

Involved persistent or significant disability

Congenita l anomaly

Importa nt Medical Event

Outcome

Congestive Heart Failure

16Mar2010

Unrelated

Ongoing

Is this event possibly related to study drug? Study drug start date

Yes, explanation of opinion: No 08 Jan 2010

Action taken with investigational product(s) as result of SAE Date study drug last taken (prior to SAE) If study drug stopped and restarted, did the event reappear?

None Dose permanently discontinued Dose interrupted Not applicable 16 Mar 2010

Yes No Not applicable

Provide a brief narrative description of SAE: On 16- Mar-2010 the patient went to the emergency room with complaints of sudden weight gain, 10 pounds over the prior week, shortness of breath, peripheral edema, and decreased exercise tolerance. He was admitted for Congestive Heart Failure. Initial treatment included Lasix 100 mg IV. Provide details of any Clinically Significant Diagnostic Procedures performed to diagnose this SAE: Laboratory Date and Time Result Units Test/Procedure Name Echocardiogram CXR Arterial Blood Gas PaO2 16-MAR-2010 16-MAR-2010 19:30 16-MAR-2010 17:05 Ejection fraction 45% Pulmonary vascular congestion; Bilateral pulmonary infiltrates 70 on 2 /L nasal cannula Normal Limits

mmHg

80-100

Subject: 045 - ADF Page: Medical History Screening Was medical history collected? Are there any medical history findings existing prior to or on entry to the trial that are considered relevant to the study? # Body System or Organ class Medical history 1 Cardiovascular Hypertension Yes Yes Onset date or date of diagnosis UNK-UNK-2005 Ongoing? Yes Date Resolved

2 3

Cardiovascular Cardiovascular

Coronary Artery Disease Peripheral arterial disease

UNK-UNK-2009 UNK-Jan-2010

Yes Yes

Subject: 045 - ADF Page: Concomitant Medication Prior/ConMeds (1) Currently viewing line 1 of 1 Name of drug, Medication or Therapy Dosage Drug Units Route of Administration Frequency Reason therapy administered Start date of therapy End date of therapy Currently viewing line 2 of 2 Name of drug, Medication or Therapy Dosage Drug Units Route of Administration Frequency Reason therapy administered Start date of therapy End date of therapy AMLODIPINE 5 MG ORAL DAILY HYPERTENSION 16-AUG-2005

LASIX 20 MG ORAL DAILY HYPERTENSION 16-AUG-2009

Subject: 045 - ADF Page: Demographics Screening (1) Birthdate Age Sex Ethnicity Weight Height 01 APR 1970 39 YEARS MALE WHITE 225 POUNDS ____

Test Case #3 - Spontaneous report from a physician (Initial Report)

Date of notification: 12-May-2010

ADR FORM FOR MARKETED PRODUCTS

Reporters Details Robert Muller, MD Occupation: Physician Relationship to above patient (e.g. self/sister/brother): Address: Hugenottenallee 167 City: Neu Isenburg Postal/Zip code: 63263 Country : Germany Tel: 49 6102 296 0 Reporter Signature: Robert Muller, MD

Patients Attending Physician Robert Muller, MD Occupation: Physician Address: City: State: Postal/Zip code: Tel: Fax:

If Consumer Report, has consumer given consent to contact their physician? Yes No Patient Details Initials: Sex: M F DOB: 04-JAN-1956 or Age / Approx. Age: Height: .................(cm) Suspect Product Suspect Product Cardiogene Overdose Y N Adverse Experience (list in order of importance) heart failure and circulatory failure Date of Administration Unknown Administration Error Y N Onset Date or Time to Onset 10-May-2010 Resolved Y/N Lot Number Unknown oral Route Weight: ...........(kg) Ethnic Origin: ........................ Pregnant: Y N N/A

If Yes please describe below Stop Date Relationship to Suspect Product (Y / N / Unknown)

Seriousness Criteria (tick all that apply) Hospitalized / hospitalization prolonged Date of admission: ..... / ..... / ..... Date of discharge: ..... / ..... / ..... Death Date: 10-May-2010....................... Cause: .......................................... Autopsy performed? Yes No Yes No Autopsy report enclosed? Life threatening Medical / surgical intervention Other: Specify ___________________________

For Health Professional use only: Disabling / incapacitating Congenital anomaly Required emergency room/doctor visit

ADR FORM FOR MARKETED PRODUCTS

Additional information (e.g. overall diagnosis, relevant investigations, previous episodes etc.): The patient's Huntington's Chorea had been progressing for the past year The patient developed syncope and died from heart failure and circulatory failure. Concomitant medications included unspecified antipsychotic drugs

Action taken (tick all that apply) Suspect product continued Suspect product dose changed Suspect product discontinued Suspect product interrupted Not applicable Yes No Not applicable Yes No Not applicable Yes No Not applicable Yes No Not applicable Treatment:

Symptoms abated on Suspect Product withdrawal? Symptoms recurred on re-exposure to Suspect Product? Previous exposure to Suspect Product? Similar events after previous exposure?

Relevant Medical History (including allergies, surgical procedures etc.) Condition / Procedure Start Date Stop Date (state if ongoing) Ongoing Jan-2010 Comment

Huntington's chorea Aspiration Pneumonia

UNK 1981 Jan-2010

Concomitant Medication (please give details of all medication taken in preceding 3 months, including over the counter medications) Drug Name Start Date Stop Date (state if ongoing) Unit Dose Frequency Route Indication

Has a Report to the Regulatory Authorities been submitted? Yes No If yes, date sent: ....../....../...... and Ref No: .................

Company Signature: ......................................................................... Date: ....../....../...... (dd/mmm/yyyy)