1

Corrected Minutes of International ITI Investigators Meeting

ASH 2009- New Orleans December 6, 2009

11:15- 12:45 Attendees: 116 Steering Committee: 15 Donna DiMichele, Charles Hay, Thomas Abshire, Gunter Auerswald, Miguel Candela, Nadia Ewing, Alessandro Gringeri, Keith Hoots, Tom Kisker, Anna Makipernaa, Claude Negrier, Keiji Nogami and, Koji Yada (for A. Yoshioka), Georges Rivard, Elena Santagostino Study Staff: 1 Ilene Goldberg DSMB: 3 Lou Aledort, Alan Giles, Inge Scharrer Centres: 37 Jussara Almeida, Carolyn Bennet, Diane Bissonnette, Manuel Carcao, Shannon Carpenter, Cheryl de Guzman, Gerry Dolan, Nancy Dower, Jenny Goudemand, Sebastian Hoegl, Robert Klaassen, Rebecca Kruse Jarres, Roshni Kulkarni, Margaret Kurth, Thierry Lambert, Cindy Leissinger, Maria Elisa Mancuso, Prasad Mathew, Shannon Meeks, Jim Munn, Anne Neff, Tim Nores, Ulrike Nowak-Gottl, Diane Nugent, Julia Philips, Steve Pipe, Margaret Ragni, Silvia Riva, Cathy Rosenfield, Chantal Rothchild, Kapil Saxena, P Carla Schinco, Frank Shafer, Marianne Sigaud, Jun-Ki Takauden, Leonard Valentino, Brian Wicklund Satellite Studies: 3 Christoph Konigs, Wander van Heerde, Bert Verbruggen Industry/Other Guests: 53 B Abuttl, R Bartels, Eva Bastida, Rachel Beer, Garrett Bergman, Paula Blackmore, Elisabeth Calov, R Chandrika, Christine Chow, ML Christianson, David Cooper, Chris Core, Roberto Crea, Cromwell, David Dasris, Gioacchino DeGiorgi, T Dunhem, Vito Ercole, Pierre-Francois Falco, Carol Goss, Heiborg, Amy Holle, David Holliday, Soenke Johannsen, Marianne Kialke, Virginia Kraus, Michele Lee, David Lillicrap, Lars Louridzen, Huong Luu, Steve McCora, Lisa Michaels, Jennifer Nad, Neuhaus, Sandra Nieto, Obergrizu, H Ogawa, Frank Parilla, Flora Peyvandi, Marc Ramby, P Ross, Barbara Rossi, Joana Sabat, Cristina Santoro, Claudia Schoenig-Diesing, Bruce Schwartz, Stephanie Seremitis, Mutsumi Shiraishi, Jamie Siegel, Jeff Spears, Gerald Spotts, Marcus Stockschlaeder, Tobias Sutter, Gigi van Denttopf, Sylvia von Mackensen, Karen Wilson, Christine Woltman (highlighted names are unclear or incomplete-affected participants welcome to clarify)

Welcome- D. DiMichele Dr DiMichele welcomed the attendees, thanked Baxter for sponsoring the meeting and thanked the RESIST study for the extra 15 minutes they provided for the meeting. A motion to approve the July 2009 meeting minutes was made by Dr Rivard and seconded by Dr Ewing. The minutes were approved. ITI Study Update- D. DiMichele Dr DiMichele began by reminding the audience of the ITI study hypothesis: For good risk severe hemophilia inhibitor patients, high dose ITI may achieve tolerance more rapidly, but may not have a greater overall success rate. The morbidity and cost-effectiveness of the two approaches is unknown but may be dissimilar. The principle analyses were also briefly reviewed. These include: the overall ITI success rate, time to ITI success and milestones, the relapse rate within 12 months of tolerance, the comparative cost effectiveness of the two arms, comparative morbidity of the two arms and the effect of pre-ITI variables such as the starting inhibitor titer and product purity. The decision to close the study was made on November 12, 2009. The data presented today will include only those subjects for whom the analyses were completed to date. Therefore although the overall study dataset will include 116 randomized subjects, the randomized arm -specific analysis will include only a subset of that cohort. Data cleaning will need to be done. Consequently, all the numbers may change after data checking is completed. The data are as follows:

Recruitment at Study TerminationRecruitment at Study Termination

133registered

6 pre-ITI phase

116randomised

11off study

pre ITI phase

60on-study

56off-study

12-Nov-09

2

248

115

24

317

623

121

322

1

0 10 20 30 40 50 60

TaiwanUSAUK

SpainNorway

New ZealandThe Netherlands

JapanItaly

IsraelFranceFinlandCanada

BelgiumAustria

AustraliaArgentina

Recruitment by Country at Study End

12-Nov-09

60on-study

29with

inhibitor

8-ve

inhibitor

4-ve inhibitor

normal recovery

19normalhalf life

12-Nov-09

3

56off-study

28tolerant

2partial

successes

13failures

13removed for other reasons

18successes

5relapses

(also partial success)

8 <20% decline

in inhibitor in 6 months

5Failure to eradicate inhibitor in 33 months

2Physician

wished to withdraw

2Parent/subject

wished to withdraw

4 grossdeviation

from protocol

5subjects fail to

comply

5Removed

post-tolerance

1subject failed

to comply

1Physician wished

towithdraw

1 Lost to

Follow up

1gross

deviation from

protocol

1Parent/subjectwished

to withdraw

12-Nov-09 The intention to treat analysis will include the 13 subjects withdrawn for other reasons after a median of 12 months on study (range 0-33 months). Of these, five subjects were in the low-dose arm and withdrawn after a median of 7 months and 8 were in the high dose arm and withdrawn after a median 17 months on study. Among these subjects, one subject was removed immediately after randomization without having any treatment. The dataset is incomplete for the 5 subjects removed post tolerance.

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Interim Analysis: Entire Cohort

Progress on StudyProgress on StudyAll Randomised Subjects (n=116)All Randomised Subjects (n=116)

Med. (range)Med. (range)

Months from diagnosis to <10 BU (n=116)Months from diagnosis to <10 BU (n=116) 5.0 (0 5.0 (0 –– 23.0)23.0)

Months on ITI (n=116)Months on ITI (n=116) 14.0 (0.8 14.0 (0.8 –– 33.0)33.0)

Months to negative titre (n=59)Months to negative titre (n=59) 6.0 (1.0 6.0 (1.0 –– 27.0)27.0)

Months ITI start to N recovery (n=51)Months ITI start to N recovery (n=51) 8.0 (2.0 8.0 (2.0 –– 32.0)32.0)

Months from ITI start to tolerance (n=47)Months from ITI start to tolerance (n=47) 15.0 (3.015.0 (3.0–– 30.0)30.0)

12-Nov-09

There is little change in these data from the previous analysis

Of the 62 subjects randomised & reaching an ITI success or failure study end-point: -

47 (76%) achieved tolerance(includes 28 subjects who completed study and 19 subjects currently on prophylaxis s/p achieving a tolerance endpoint)

2 (3 %) achieved partial success13 (21%) were failures

An ITT analysis will show only 64% success when the following subjects are also included:

12 removed post-randomisation for other reasons; logistic or compliance.

12-Nov-09

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Mean Med. Mean Med. (Range)(Range)

Recovery (%)Recovery (%) 9191 8686 (66 (66 –– 183)183)

Half life (hours) Half life (hours) 88 7 7 (6 (6 -- 15)15)

12-Nov-09

5 subjects relapsed on prophylaxis3/5 negative BU but shortened half life / recovery.Two normalised PK and BU negative on prophylaxis.Two normalised PK and BU negative on prophylaxis.Demographically similar to nonDemographically similar to non--relapsed subjectsrelapsed subjectsAll meet criteria for a partial success.All responding to treatment with no anamnestic All responding to treatment with no anamnestic increase in inhibitor.increase in inhibitor.

2 subjects 33 months on study without normal recovery and half life but with negative Bethesda titre

Responding to factor VIII without anamnesis.Responding to factor VIII without anamnesis.12-Nov-09

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The product choice is that of the patient’s managing physician.

104/116 patients using recombinant (90%)

12/116 patients using plasma derived (10%)

*These figures are based on details given at randomisation

12-Nov-09

Interim Efficacy Analysis by Treatment Arm The following analysis is performed on data from 110/116 randomized subjects and numbers may change after data checking.

`

Subject Demographics for all Randomised Subject Demographics for all Randomised Subjects by Treatment Arm: n=110Subjects by Treatment Arm: n=110

Median Median Low Dose High DoseLow Dose High Dose(n=55) (n=55)(n=55) (n=55)

Randomisation age (mos) Randomisation age (mos) 23.123.1 21.521.5

Diagnostic Inhibitor Titre Diagnostic Inhibitor Titre 9.79.7 11.511.5

Peak Historical TitrePeak Historical Titre 19.119.1 22.022.0

Titre at the start of ITITitre at the start of ITI 5.75.7 5.15.1

Peak inhibitor titre on ITI Peak inhibitor titre on ITI 37.437.4 30.130.1

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Low Low HighHigh pp

–ve BU titre n=26 n=2610.0 (3.1-26.1) 3.3 (1.4-33.6) 0.002

Normal recovery n=23 n=2213.9 (2.9-28.4) 3.9 (2.5-29.5) 0.0013

Normal ½ -life n=21 n=2215.6 (6.1-30.4) 9.2 (3.5 -29.5) 0.061

There is a statistically shorter time in the high dose cohort to the achievement of negative titer and recovery ITI milestones Although time to achievement of normal half life remains shorter in the high dose group, the difference loses statistical significance.

Further Analyses Among Randomised Subjects by Further Analyses Among Randomised Subjects by Treatment Arm:Treatment Arm:

Low Dose High DoseLow Dose High Dose#Subjects#Subjects 2121 2222Recovery at toleranceRecovery at tolerance (% exp)(% exp)

•• MedianMedian 8686 8181•• RangeRange (69(69--136) (66136) (66--183)183)

Half Life at toleranceHalf Life at tolerance (hours)(hours)•• Median Median 77 77•• RangeRange (6(6--15)15) (6(6--12)12)

#Relapses on Prophylaxis #Relapses on Prophylaxis 22 33

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104/116 patients using recombinant (90%)(Low Dose: 53; High Dose: 51)

12/116 patients using plasma derived (10%)( Low Dose: 6; High Dose : 6)

12-Nov-09

Successful Tolerance (n/%) Among Randomised Successful Tolerance (n/%) Among Randomised Subjects by Treatment Arm: ITT analysis: n=110Subjects by Treatment Arm: ITT analysis: n=110

Low Dose Low Dose High Dose ORHigh Dose OR

At 9 mths on ITIAt 9 mths on ITI 4/53 (9%) 4/53 (9%) 11/50 (23%) 3.111/50 (23%) 3.1

End of StudyEnd of Study 21/55 (56.7%)21/55 (56.7%) 22/55 (57.2%) 1.122/55 (57.2%) 1.1

Slower ITI in lowSlower ITI in low--dose arm.dose arm.Similar end of study successSimilar end of study success--rate in each arm.rate in each arm.Low success may reflect many subjects in early phase of ITI Low success may reflect many subjects in early phase of ITI

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Importantly, the original estimation of study cohort size of 75 subjects/ arm was calculated on the basis of the existing literature that suggested that we could anticipate a success rate of 80% in the high dose arm and 50% in the low dose arm, 9 months after the initiation of ITI (difference of 30%). The actual ITI success rates at that time point are lower and less discrepant than anticipated. The odds ratio of achieving success early in the course was 3.1 and statistically significant. However, there is no statistical difference in overall success rates at the end of study. This is further illustrated in the following Kaplan–Meier analyses below:

0 1 2 3 4

Time in Years

0

20

40

60

80

100

% Not reaching tolerance

Low (n=55)High (n=55)

Extended censoring on cases unable to reach tolerance

P=0.732

If considering only those subjects who achieved defined success or failure endpoints (and not withdrawn for other reasons), there remains no difference in the 2 arms of Kaplan-Meier plot below and the success rate approximates 70%. However, the lack of difference does not mean equivalence, as the study does not have sufficient recruitment to have the power to demonstrate equivalence. The current estimate of # subjects required per arm, given the actual success rates achieved at 9 months on study is > 300 as illustrated in the second slide below:

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0 1 2 3 4

Time in Years

0

20

40

60

80

100

% not reaching tolerance

Low (n=52)

High (n=50)

% subjects not reaching tolerance

P=0.766

Sample Size Estimation:Testing for Equivalence

The numbers in the cells are the number needed in each arm.Higher efficacy requires larger sample size to demonstrate equivalence.Wider boundaries (e.g. 30% efficacy +/- 20%) require smaller sample size.

Expected rateExpected rate Boundary of equivalenceBoundary of equivalenceof toleranceof tolerancefor each armfor each arm ±5% ±10% ±15% ±20%

50% 1568 392 175 98

30% 1318 330 147 83

10% 565 142 ----- -----

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Data Safety Report: C Hay on behalf of the DSMB CATHETER INFECTIONS – cumulative safety data for the whole cohort

254 serious adverse events254 serious adverse events(253 of which are hospitalisations)(253 of which are hospitalisations)

32 judged by DSMB to be study32 judged by DSMB to be study--relatedrelated30 catheter30 catheter--related SAEs:related SAEs:

4 catheter related bleeds4 catheter related bleeds9 infections in 6 subjects9 infections in 6 subjects12 insertions/removals12 insertions/removals1 subclavian vein thrombosis1 subclavian vein thrombosis2 malfunctioning catheters2 malfunctioning catheters2 ruptures of suture site2 ruptures of suture site

1 trauma1 trauma1 possible reaction to FVIII (product related1 possible reaction to FVIII (product related)

Recent SAEs awaiting full data submission for DSMB Recent SAEs awaiting full data submission for DSMB adjudicationadjudication

Catheter SAE’s were determined to be study related if the catheter was inserted specifically for immune tolerance on the study

114 catheter114 catheter--related SAEs:related SAEs:7 catheter related bleeds7 catheter related bleeds60 catheter infections in 19 subjects60 catheter infections in 19 subjects39 insertions and/or removals39 insertions and/or removals1 subclavian vein thrombosis1 subclavian vein thrombosis7 other catheter7 other catheter--related problemsrelated problems

61 bleeds requiring hospitalisation in 29 subjects61 bleeds requiring hospitalisation in 29 subjects1 death on study from traumatic intracranial haemorrhage.1 death on study from traumatic intracranial haemorrhage.11 non11 non--catheter related infections in 11 subjectscatheter related infections in 11 subjectsOther: Other: --

5 haematomas; 1 ear infection; 2 dental extractions; 9 5 haematomas; 1 ear infection; 2 dental extractions; 9 traumas; 3 surgeries; 6 PUO; 2 bronchospasms; 1 traumas; 3 surgeries; 6 PUO; 2 bronchospasms; 1 possible reaction to FVIII infusion (product related); 1 possible reaction to FVIII infusion (product related); 1 Anaemia; 1 for start of ITI; 1 Anaemia; 1 for start of ITI; 1 ““pale after infusionpale after infusion””; 2 ; 2 vomitingvomiting

* Further SAE’s awaiting data completion for DSMB adjudication

Serious Adverse Events (7/09)*Serious Adverse Events (7/09)*Non StudyNon Study--related (n=221)related (n=221)

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93 catheter related events in 31 subjects41 for infections not requiring hospitalisation41 for infections not requiring hospitalisation13 for swelling around port site13 for swelling around port site8 for irritation around site8 for irritation around site16 for blocked/stiff line16 for blocked/stiff line5 for discharge around catheter5 for discharge around catheter4 for cracked lines4 for cracked lines1 for pain around catheter1 for pain around catheter5 haematoma after catheter use5 haematoma after catheter use

12-Nov-09

Catheter (CVAD) Placement:Catheter (CVAD) Placement:

93/133 registered subjects have or had 156 CVADs93/133 registered subjects have or had 156 CVADs

68 /93 (73%) subjects had CVADs pre68 /93 (73%) subjects had CVADs pre--registrationregistration

46/59 subjects on study currently have catheters46/59 subjects on study currently have catheters

Median (range) of 1 catheter (1Median (range) of 1 catheter (1--8) per subject8) per subjectMean of 2 catheters per subjectMean of 2 catheters per subject

12-Nov-09

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112 line infections in 38 subjects (1112 line infections in 38 subjects (1--11 /subject )11 /subject )71 judged SAEs and 41 AEs 71 judged SAEs and 41 AEs (managed as outpatient)(managed as outpatient)Many subjects with apparently repeated infection had Many subjects with apparently repeated infection had several episodes with a single organism.several episodes with a single organism.These may represent a single infection incompletely These may represent a single infection incompletely eliminated.eliminated.Some infections were treated with oral antibiotics on Some infections were treated with oral antibiotics on an outpatient basisan outpatient basis

10 haematoma/swelling around port in 10 subjects10 haematoma/swelling around port in 10 subjects2 subclavian thromboses2 subclavian thromboses51 line insertions/removals in 32 (1 51 line insertions/removals in 32 (1 –– 4/subject)4/subject)

2 for rupture of suture site.2 for rupture of suture site.

12-Nov-09

Catheter Infections:Catheter Infections:156 catheters placed in 93/133 subjects156 catheters placed in 93/133 subjects

89 Portacaths, 28 Broviac/Hickmans, 26 PICCs and 13 89 Portacaths, 28 Broviac/Hickmans, 26 PICCs and 13 unknownunknown

Out of 79 subjects with completed questionnaires,Out of 79 subjects with completed questionnaires,63 had catheters placed for clinical need (for Prophy. pre63 had catheters placed for clinical need (for Prophy. pre--study).study).16 had catheters placed for study need (for ITI)16 had catheters placed for study need (for ITI)

Catheter infection developed in 38/93 subjectsCatheter infection developed in 38/93 subjectsAfter a median of 234 days (range: 11 After a median of 234 days (range: 11 –– 996 days) 996 days) Median age at randomisation of infected and uninfected subjects Median age at randomisation of infected and uninfected subjects was 21 and 25 months, respectivelywas 21 and 25 months, respectivelyInfected subjects had a median 2 (1Infected subjects had a median 2 (1--11) infections.11) infections.Infected subjects had a median of 1 (1Infected subjects had a median of 1 (1--8) catheters.8) catheters.

12-Nov-09

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0 1 2 3 4

Time in Years

0

20

40

60

80

100

PORT (n=53)HICK/BROV (n=10)

Time to first infection by type of catheter

% Free of infection

53 Portacaths10 BroviacsP=0.18

Catheter Infections: Interim Safety Analysis by Treatment Arm- Note: Cumulative rate of catheter Infection by treatment arm not available at time of this presentation. However, the following analyses were done:

0 1 2 3 4

Time in Years

0

20

40

60

80

100

% F

ree

of fi

rst i

nfec

tion

High (n=44)

Time to first Catheter Infection by arm

P=0.907

Low (n=42)

No statistical significance between dosing arms noted for time to first catheter infection

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No Infection Infection pTo –ve BU titre n=28 n=18

5.5 (1.8-33.6) 7.6 (1.4-25.5) 0.437

To normal recovery n=20 n=1613.8 (2.8-30.1) 16.3 (3.2-29.5) 0.408

To normal half-life n=23 n=1614.9 (3.5-27.7) 13.7 (3.5-29.5) 0.368

Time on ITI n=53 n=3315.4 (2.9-35.3) 15.9 (6.0-35.6) 0.176

No statistically significant difference in the time to achievement of any ITI parameters were noted between the two arms HEMORRHAGE: Cumulative Safety Data for the Entire Cohort

72 bleeds in 34 subjects reported72 bleeds in 34 subjects reportedmedian (range) per subjectmedian (range) per subject 1 (1 1 (1 -- 11)11)median (range) per subject/yr on ITI 1 (0.3 median (range) per subject/yr on ITI 1 (0.3 –– 8.0)8.0)

Haemarthroses Haemarthroses 2727Muscle bleeds Muscle bleeds 1414Face/head (Minor trauma) Face/head (Minor trauma) 33NoseNose 88MouthMouth 55Port/BroviacPort/Broviac 1111OtherOther 11Unspecified site Unspecified site 22

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874 bleeds in 82 subjects reported874 bleeds in 82 subjects reportedmedian (range) per subjectmedian (range) per subject 7 (1 7 (1 -- 64)64)median (range) per subject/yr on ITI 7 (0.6 median (range) per subject/yr on ITI 7 (0.6 –– 40.0)40.0)

Haemarthroses Haemarthroses 391391 Other Other 1010Muscle bleeds Muscle bleeds 157157 UnspecifiedUnspecified 1515Face/head Face/head (Minor trauma)(Minor trauma) 145145NoseNose 2121MouthMouth 6060Port/BroviacPort/Broviac 7575

12-Nov-09

HEMORRHAGE: Interim Safety Analysis by Treatment Arm

Among 54 LowAmong 54 Low--dose and 55 highdose and 55 high--dose subjectsdose subjectsLow Dose Arm: 583 bleeds Low Dose Arm: 583 bleeds High Dose Arm: 212 bleedsHigh Dose Arm: 212 bleeds

Follow Up Period Hazard Ratio (95% CI) p value Full F/U 2.56 (1.61-4.07) 0.000067Truncated F/U* 1.94 (1.1-3.44) 0.023

Excluding subjects on bypass therapy prophylaxis**Full F/U 2.34 (1.4-3.9) 0.0011

*Truncated follow-up was explored because of concerns about interpretation of follow-up and truncates follow-up to one day after the last reported bleed.** Analysed as a potential statistical confounder.

A statistically higher rate of bleeding in the low dose arm compared to the high dose cohort was observed: Prophylaxis did not appear to be a confounder

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Frequency of bypass therapy prophylaxis Frequency of bypass therapy prophylaxis during ITI by treatment armduring ITI by treatment arm:

Low Dose Arm High Dose Arm 8/54 (15%) 2/55 (4%)

Prophylaxis was not anticipated by the Prophylaxis was not anticipated by the protocol and neither mandated nor prohibitedprotocol and neither mandated nor prohibited

Circumstances of use of prophylaxis ( prior to or in response to bleeding) not yet analyzed

Full F/U Regimen # Bleeds Hazard-Ratio (95% CI) pAll ITI low-dose 583 2.56 (1.61-4.07) 0.000067(n=54v55)(n=54v55) high-dose 212

Part 1 (54v55) low-dose 475 2.50 (1.37-4.55) 0.0027(To Neg BU) high-dose 179

Part 2 (26v26) low-dose 40 6.01 (2.39-15.1) 0.0014(To Norm Rec.) high-dose 23

Part 3 (23v22) low-dose 12 too few for analysis(To Tolerance) high-dose 0

Part 4 (21v22) low-dose 56 5.88 (2.11-16.4) 0.00071(Prophylaxis) High-dose 10

In every phase of the study there was a statistically higher rate of bleeding in the low dose arm (except in Part 3 too few to analyze)

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The same trends were noted for joint and muscle bleeds when analyzed separately (the next two slides)

Full F/U Regimen #Bleeds Hazard-Ratio (95% CI) pAll ITI low-dose 286 2.51 (1.42-4.42) 0.0015(n=54v55)(n=54v55) high-dose 97

Part 1 (54v55) low-dose 218 2.45 (1.20-5.00) 0.014(To Neg BU) high-dose 87

Part 2 (26v26) low-dose 28 too few(To Norm Rec.) high-dose 8

Part 3 (23v22) low-dose 3 too few(To Tolerance) high-dose 0

Part 4 (21v22) low-dose 37 16.2 (3.38-77.3) 0.00049(Prophylaxis) High-dose 2

Full follow-up Regimen #Bleeds Hazard-Ratio (95% CI) pAll ITI low-dose 130 2.63 (1.41-4.93) 0.0025(n=54v55)(n=54v55) high-dose 45

Part 1 (54v55) low-dose 112 2.58 (1.28-5.21) 0.0083(To Neg BU) high-dose 40

Part 2 (26v26) low-dose 5 too few(To Norm Rec.) high-dose 1

Part 3 (23v22) low-dose 2 too few(To Tolerance) high-dose 0

Part 4 (21v22) low-dose 11 too few(Prophylaxis) High-dose 4

l

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0 200 400 600 800 1000 1200 1400

05

1015

P = 0.000067

Cumulative Days at Risk per Treatment Arm

Low Dose

High Dose

The differential rate of bleeding between arms was noted early and worsened over time On the basis of the statistically significant differential rate of bleeding noted between the two treatment arms both early and late in the course of ITI, the DSMB recommended that the International ITI Study be prematurely terminated due to safety concerns. After the PIs carefully considered the DSMB recommendation, their decision was to follow the DSMB’s unanimous recommendations and to stop the study on November 12, 2009. The data and rationale for this decision was presented to and approved by the International ITI Study Steering Committee immediately prior to the Participant’s Meeting

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CONCLUSIONS: based on the Interim Arm to Arm Comparison

EfficacyEfficacyAs per our original hypotheses, low dose ITI

subjects achieved tolerance more slowly than high dose subjects

However, there was no difference in overall success rate at 33 mos

Importantly, success rates in both arms were lower than would have been predicted by the literature

MorbidityMorbidityAs per our hypothesis, morbidity was indeed

dissimilar between armsPerhaps surprisingly catheter infections occurred

with similar frequency in both treatment arms and did not appear to affect outcome

Significantly more bleeding was observed in the low dose arm at all stages of ITI but most impressively prior to achievement of a negative inhibitor titre

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Study PowerStudy PowerThe original power calculations for this study

were based on ITI overall success rates and time to success for high and low dose therapy as reported in the literature

In fact, although the hypothesis was correct , the less discrepant rates of early success at 9 months would mandate an enrolment that far exceeds potential for recruitment

Decision to Stop the Study:Decision to Stop the Study:Justified on the basis of:

1.Significantly differential bleeding morbidity between the two arms

2. Insufficient statistical power to prove equivalence

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DSMB COMMENTARY The DSMB had no additional comments after the presentation GROUP DISCUSSION In response to a question from Dr Auerswald about whether the bleeding frequency in the small group of subjects who used bypass therapy prophylaxis in either arm was known, Dr Hay responded that it was but not presented because the numbers were small, and the bleeding rates variable and difficult to interpret at this time. Also, more than 1 bypassing agent was used because the choice of product was up to the clinician, further confounding any interpretation. Prophylaxis use was not a confounder, even though there was a difference in the 2 treatment arms in the number of patients and proportion of patients on prophylaxis. In terms of analyzing efficacy of prophylaxis, the bleeding rates before and on prophylaxis would have to be dissected and that has not been done. The Bonn protocol empirically used prophylaxis until the inhibitor titre was negative and then it was stopped, and that was based on empirical observation that bleeding frequency falls off at that point. In this study, the bleeding frequency did not make a difference to ITI outcome. You have a 2 ½ fold difference in bleeding frequency between the 2 treatment arms with no difference in ITI outcome. Dr Santagostina suggested that the greater number of bleeds in the low dose arm reflected the longer time taken for low dose ITI to achieve tolerance. Dr Hay replied that we would look at this further but the preliminary analysis of the data suggested that although the low dose arm subjects did indeed take longer to achieve tolerance, the bleed-rate per unit time was still greater in the low-dose arm. Bleeding frequency will be further analyzed by the different phases of the study. Dr Aledort added that throughout the whole time on study subjects bled more on the low dose arm. Bleeding into the joints was of particular concern, and combined with the likelihood of not being able to come out with an equivalency answer for the study, the DSMB made the decision they did regarding study closure. Dr Ragni asked if the time to catheter infection was measured from the time the catheter was placed, not from ITI initiation. Dr Hay confirmed that it was and Dr DiMichele added that the catheter infection rate could also be looked at from the time ITI was started. Dr Nugent asked why the odds ratio was so high in the prophylaxis phase when the subjects were now on the same dose. She further wondered whether the low dose group was actually a higher bleeding group or was that differential perhaps a result of low numbers. Dr Hay said that will have to be investigated further. He clarified that the high dose group was on the prophylactic dose for 9 months due

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to the taper while the low dose subjects went onto low dose prophylaxis immediately following tolerance and stayed on for the full 12 months. We will have to look at where most bleeding occurred in the 12 month period. He suggested that the low dose group could also have had more bleeding post tolerance due to the development of arthropathy. That will have to be examined. Finally, the prophylactic regimen in the protocol was the also the standard at the time, but by many people’s standards today it might be considered a relatively low dose. Dr Aledort also suggested that another way to interpret this was that the low dose group bled more on the same prophylaxis dose because by the time they got to the prophylaxis stage they had more joint disease, which caused them to bleed more. Perhaps if they had fewer haemarthroses on ITI they would have had fewer bleeds on prophylaxis. Dr DiMichele added that there was a need for sub analyses to be done to identify at what point in the prophylaxis phase bleeding occurred and if these were repeated bleeds into single joints. She also wanted the group to know the DSMB cautioned them about the analysis of prophylaxis, largely because of the small number of subjects who were on it and also because the data is subject to interpretation. However, since the PIs knew that this group would consider it to be such an important question it was mentioned in respect to its effect on the overall statistics. Dr Carcao asked if there was a difference between the 2 groups in terms of total number of line infections and average number of infections per subject. Dr DiMichele said that it appeared not but that the catheter infection data was complex and required further analysis. Dr Kulkarni asked if there was clinical correlation between line infections and joint disease. Might some haemarthrosis actually be infectious complications? Dr DiMichele responded that data could be examined, but probably not. No joint infections had been reported. Dr Gringeri felt it was premature to close the study and there should have been a warning sent to the investigators to consider this difference in bleeding frequency between the two arms. He didn’t agree with the sudden stoppage of the study and thought there should have been greater insight into the data and a longer discussion at this meeting before the decision was made. Dr Rivard stated that he had come to the meeting concerned that the study was stopped so quickly, but after looking at the data, he was convinced that it was the correct thing to do. He had not anticipated this outcome of more bleeding, but now what does it mean in terms of clinical or long term joint outcome? It was no surprise to see more bleeding if a patient goes for some time without FVIII coverage. He was sorry the study has to end but felt it is the right thing to do. Dr Cacao stated when the email was received many people were left wondering why the study was closed. Looking at the data at this time, most people are

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probably convinced the study should be closed. But that was not the case 3 weeks ago when very little data was provided. A hazard ratio doesn’t mean that much without actual numbers. Given that the decision was made only 3 weeks before the meeting was to occur, perhaps there were other ways to have handled the situation such as providing more information, if it was available, or stopping enrollment until it could be discussed at this meeting. He also expressed concern that people would take away the idea that high dose therapy is better, when it may actually be high frequency that is protective against bleeding. Daily therapy may be more effective than three times a week in preventing bleeding. Dr Hay responded that they had many conference calls with the DSMB, meetings with the statistician, and they were advised the study should be closed. They considered closing to recruitment only, but they were finally convinced by the combination of the inability to achieve statistical significance for efficacy and the fact there was more bleeding throughout the study into the prophylaxis stage. In terms of procedure, the decision to close the study is clearly the responsibility of the Principal Investigators and they felt it would be an ethical issue if they waited. Dr DiMichele clarified that the data presented at the meeting was the data they had when they made the decision. One of the reasons immune tolerance is done is to prevent bleeding morbidity, so if there was discrepant morbidity people needed to know as soon as possible for ethical reasons. There is a fine line between sending out enough information versus too much information without benefit of explanation to justify the decision and she apologized if people felt they did not receive enough information. Dr Rivard agreed with Dr Carcao that people must be careful about the final message on how immune tolerance is done. Dr DiMichele agreed and said that is where the group will have input, in writing up the data, that is where the data will be discussed and interpreted. Dr Kisker will be speaking about this shortly. Data/Sample Collection and Ethics IRB issues Logistics going forward- D DiMichele The coordinators –Ilene Goldberg in the US and Matt Foulkes for the International centres- will send out instructions for the centres IRB/ethics committees

• Centres without enrolled subjects should close the study at their centres • Centres that had subjects enrolled:

o Close the study to enrollment and treatment, but keep open for data collection

o US centres should continue to get approval for Amendment 4 o The Amendment for International centres will be dispersed when

available. • DSMB report to be sent when finalized

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Data Collection • All data through November 12, 2009 should be entered on the web site by

March 1, 2010 • Paper CRF s will be sent to US centres to record retrospective and follow-

up data on subjects who have consented (Amendment 4 US protocol) Sample collection

• Confirmatory inhibitory samples ( Pre- ITI inhibitors < 10 BU, 1st 2 negative inhibitor titres on ITI, and 12 month monitoring for relapse inhibitor titre) should be sent to the US and International repositories by March 31, 2010

• Inhibitor samples from subjects who consented to repository sample use

should be sent to the appropriate repository by March 31, 2010. Appropriate samples will be sent to satellite study investigators. We will have a better idea what samples are available after all the samples are at the repository. If the satellite investigators have any questions about the status of their studies or samples they should contact the coordinating centers.

Proposed Observational Study for Ongoing Cohort – D DiMichele Dr DiMichele asked the group its opinion about the kind of obligation we have to collect data on the 60 subjects who were on study at time of closure. It is not to add to the statistical analysis of the main data, because of inherent biases of doing that. Do we want to report on this cohort in an observational way? It would require another amendment. There were no comments, so the group was asked to think about it and we would address this again at a later time. In response to a question from Dr Carpenter about collecting follow-up bleeding information on these patients, Dr DiMichele responded that it is possible, but whether it would require an amendment or a separate protocol needs further deliberation. In response to a question from Dr Bergman asking if they would consider switching all the patients to a high dose arm via an amendment, Dr DiMichele responded that this had been considered. However since the investigators had been asked to make a regimen decision based on what was best for their patient, this would introduce biases in the data interpretation. An observational study going forward would be an interesting way to see what happened with those subjects, but it would take time and require IRB approval and consent. Scientific and Publications Committee- T. Kisker At the beginning of the study the following process was set up whereby investigators within the group can request data for further analyses.

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INTRODUCTIONINTRODUCTION

Prior to initiation of analysis, the items listed below should be completed in collaboration with the members of the writing group and addressed to the Publications Committee Chair (C. Thomas Kisker, M.D.) or Co-Chair (George Rivard)

ITEMS FOR COMPLETIONITEMS FOR COMPLETION

Working title of manuscript.Writing group chair and members of the writing group.Research questions or hypotheses to be addressed by the analysis.All Data Variables to be included in the analysis should be defined (i.e., initial inhibitor level, time to tolerance, genetic defect). The variables should include those obtained from the primary study as well as those obtained as part of a new study protocol.Site and Personnel who will be doing the analysis.Data requests should be addressed to C. Thomas Kisker, M.D., Chair, Publications Committee c-kisker@uiowa.edu or George Rivard, M.D. Co-chair Publications Committee rivardge@medclin.umontrael.ca

The following guidelines have been prepared for collaborators who have volunteered to be Chairs of writing committees. These guidelines have been reviewed and agreed upon by the Executive Committee and the Chair of the Publications Committee. Unless otherwise noted, all references in this guideline to the “Chair” refer to the writing committee Chair.

The writing committee Chair should expect to be first author of the paper, unless s/he designates another committee member to fill this role. The first author should expect to take responsibility for organizing and planning the paper content, as well as for doing substantial writing and having final editorial approval on the manuscript before it goes to the Publications Committee. In general, the Chair should expect to take scientific leadership and responsibility for the paper.

The Chair should work with committee members to assign tasks, e.g., literature review, data requests, liaison with others, and the writing of various sections of the paper. Members are responsible to the Chair for completing their assigned tasks by an agreed deadline so that work can proceed. The chair can reassign a task if it is not completed or is not completed adequately.

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It is recognized that not all committee members will contribute equally to a given paper. The Chair should make an effort to assess who is most interested in and familiar with the paper topic area, as an aid to determining authorship. It is recommended that order of authorship be at least roughly determined when assignments are made, so that members will know what to expect. A job of the Chair will be to minimize arguments after the fact about whose job was the most important. If participants have a good idea what their order will be (e.g. first versus third author), they will be better able to adjust their expectations.

The Chair is responsible for knowing and following study guidelines about data requests, publications, and presentations.

The Chair and other committee members should be aware that contributions from other arms of the study will also require acknowledgment, in many cases by co-authorship.

It is not expected that committees will need to meet in order towork. Chairs should communicate by conference calls, email, mail, and fax.

Give assurance that all co-authors have signed off on the manuscript.

Submit the manuscript to Publications Committee chair.

Review all manuscripts for accuracy, consistency and completeness.

Send comments to author with a copy of comments to the Executive Committee.

Respond to all comments raised by members of the Publications Committee and send copies of responses to the Executive Committee.

Send revised manuscript to the Executive Committee.

Appoint a subcommittee for review of each manuscript for scientific integrity.

Subcommittee reviews the final revised manuscript, comments, and responses.

Give final approval to principal author to submit manuscript to the journal.

Writing Writing ChairChair

Publications Publications committeecommittee

Executive Executive CommitteeCommittee

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Conclusion- C Hay Dr Hay thanked Baxter and all industry sponsors for their support throughout the many years of this study, the DSMB for all their hard work, the Steering Committee for their support, participant investigators and study coordinators for their hard work and the RESIST study colleagues for yielding time to the ITI study meeting. The next meeting will be held during WFH in Buenos Aires. Dr Kisker thanked Dr.Hay and Dr DiMichele for the years of hard work on the study. Meeting was adjoined Addendum: Dr DiMichele forgot to announce the following: For those investigators who have recently started their patients on Immune Tolerance with Advate and want to record their progress they may want to consider enrolling them in the Prospective Advate Immune Tolerance Induction Registry (PAIR). You can contact Gerald Spotts at gerald_spotts@baxter.com or Huong Luu at huong_luu@baxter.com to learn more about the registry

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