Trial Outcomes & Findings for Treatment With Infliximab in a Medical Setting (Study P05587) (NCT NCT00752622)

Last Updated: 2017-04-13

Results Overview

The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \~600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Participants provided completed CDAI diary cards and were considered as responders in the interventional phase if their CDAI score at week 24 was decreased by 70 points or greater over their CDAI score at randomization into the interventional phase, or if their week 24 CDAI score is \<= 150. Baseline is value at randomization.

Recruitment status

TERMINATED

Study phase

PHASE4

Target enrollment

100 participants

Primary outcome timeframe

Baseline and Week 24 of the Interventional phase

Results posted on

2017-04-13

Participant Flow

Of the 100 enrolled participants, 2 participants experienced a protocol violation that excluded them from the Eligible (ELIG) population, thus, the ELIG population comprised of 98 participants. Due to early study termination, all 8 randomized participants received at least one infusion of interventional treatment, but none completed the trial.

Participant milestones

Participant milestones
Measure	Infliximab Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase.
Induction Phase STARTED	100
Induction Phase COMPLETED	65
Induction Phase NOT COMPLETED	35
Observational Phase STARTED	65
Observational Phase COMPLETED	22
Observational Phase NOT COMPLETED	43
Interventional Phase STARTED	8
Interventional Phase COMPLETED	0
Interventional Phase NOT COMPLETED	8

Reasons for withdrawal

Reasons for withdrawal
Measure	Infliximab Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase.
Induction Phase Adverse Event	3
Induction Phase Other	3
Induction Phase Non-responder	14
Induction Phase Withdrawal by Subject	1
Induction Phase Premature study termination	14
Observational Phase Premature Study Termination	36
Observational Phase Non-responder	2
Observational Phase Withdrawal by Subject	2
Observational Phase Adverse Event	1
Observational Phase Other	2
Interventional Phase Non-responder	2
Interventional Phase Physician Decision	1
Interventional Phase Premature Study Termination	5

Baseline Characteristics

Treatment With Infliximab in a Medical Setting (Study P05587)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Infliximab n=100 Participants Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase.
Age, Continuous	38.4 years STANDARD_DEVIATION 13.16 • n=93 Participants
Sex/Gender, Customized Female	54 participants n=93 Participants
Sex/Gender, Customized Male	44 participants n=93 Participants
Sex/Gender, Customized Excluded from analysis	2 participants n=93 Participants

PRIMARY outcome

Timeframe: Baseline and Week 24 of the Interventional phase

Population: Due to the early termination of the study, no participants completed the Interventional phase.

Outcome measures

Outcome data not reported

PRIMARY outcome

Timeframe: Baseline and Evaluation Week 10, Week 30 and Week 54 of the Observational Phase

Mean change in HBI score from Baseline to Week 10, 30, and 54. HBI score consists of clinical parameters: general well-being (0-4), abdominal pain (0-3), number of liquid stools per day, abdominal mass (0-3), and complications (score 1 per item). Total score is the sum of individual parameters. Minimum score is 0 and no pre-specified maximum score as it depends on the number of liquid stools. Lower scores indicate better well being. Clinical response/ long-term response is defined as a decrease by 3 or more points from baseline value. Loss of response is defined as an increase of \>= 3 points.

Outcome measures

Outcome measures
Measure	Infliximab n=98 Participants Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase.
Mean Change From Baseline in Harvey-Bradshaw Index (HBI) Baseline (n= 98)	9.5 score on a scale Standard Deviation 3.23
Mean Change From Baseline in Harvey-Bradshaw Index (HBI) Change at Week 10 (n= 81)	-5.88 score on a scale Standard Deviation 3.890
Mean Change From Baseline in Harvey-Bradshaw Index (HBI) Change at Week 30 (n= 37)	-7.19 score on a scale Standard Deviation 2.998
Mean Change From Baseline in Harvey-Bradshaw Index (HBI) Change at Week 54 (n= 15)	-7.93 score on a scale Standard Deviation 3.173

SECONDARY outcome

Timeframe: Week 54 in the Observational Phase

Population: The eligible (ELIG) population comprised a subset of the enrolled (ENR) population who were not associated with an important protocol violation and who received at least one dose of study medication. Of the 98 participants in the ELIG population, 65 participants entered the observational phase.

Participants required treatment-optimization if: * Disease progression/lack of response after entering observational phase; or * Participant was successfully randomized into the interventional phase The definition of loss of response was as follows: \- An increased HBI score \>= 3 points over the week 10 evaluation score and a CDAI score \>= 175. Despite: * having received regular infusions of infliximab every 8 weeks during the observational phase with a maximum interval of no \> 10 weeks between each infusion, and * having received previous doses of infliximab of \>= 4.7 mg/kg.

Outcome measures

Outcome measures
Measure	Infliximab n=65 Participants Infliximab 5mg/kg intravenously (IV) at weeks 0, 2 and 6 during the induction phase and every 8 weeks during the observational phase and either 5mg/kg every 6 weeks or 7mg/kg every 8 weeks as determined by randomization at entry into the interventional phase.
Number of Participants That Required Treatment Optimization in the Observational Phase	10 Participants

SECONDARY outcome

Timeframe: Baseline and Weeks 14-16 and 48 in the Interventional Phase

Population: Due to the early termination of the study, no participants completed the Interventional phase.

The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \~600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 70-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at week 14-16 and 48 in the Interventional Phase. Baseline is value at randomization.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and Weeks 14-16, 24 and 48 in the Interventional Phase

Population: Due to the early termination of the study, no participants completed the Interventional phase.

The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \~600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical response was defined as a 100-point reduction in CDAI score from randomization into the interventional phase or CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase. Baseline is value at randomization.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Weeks 14-16, 24 and 48 in the Interventional Phase

Population: Due to the early termination of the study, no participants completed the Interventional phase.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Weeks 14-16, 24 and 48 in the Interventional Phase

Population: Due to the early termination of the study, no participants completed the Interventional phase.

Number of participants who were in clinical remission and off systemic corticosteroids at visit. The CDAI incorporates 8 items that are indicators of disease severity. Scores range from 0 to \~600; higher scores indicate worse disease activity. Participants with scores below 150 have inactive disease whereas those with scores above 450 are considered critically ill. Clinical remission was defined as CDAI \< 150 at weeks 14-16, 24 and 48 in the Interventional Phase.

Outcome measures

Outcome data not reported

Adverse Events

Infliximab 5 mg/kg Then Not Randomized

Serious events: 7 serious events

Other events: 42 other events

Deaths: 0 deaths

Infliximab 5 mg/kg Then Randomized

Serious events: 3 serious events

Other events: 7 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Infliximab 5 mg/kg Then Not Randomized n=92 participants at risk Infliximab 5 mg/kg IV at weeks 0, 2 and 6 during the induction phase as well as every 8 weeks during the observational phase. Participants who were further randomized into the interventional phase are not included in this reporting group; therefore, of the 100 enrolled participants, 92 participants were included in this safety reporting group.	Infliximab 5 mg/kg Then Randomized n=8 participants at risk Infliximab 5 mg/kg IV at weeks 0, 2 and 6 during the induction phase as well as every 8 weeks during the observational phase. Participants were then randomized to receive 5 mg/kg every 6 weeks (shortened interval group) or 7 mg/kg every 8 weeks (increased dose group) at entry into the interventional phase. This reporting group included 3 participants randomized into the shortened interval group and 5 participants randomized into the increased dose group.
Gastrointestinal disorders Anal Fistula	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Crohn's Disease	2.2% 2/92 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Intestinal Obstruction	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Intestinal Perforation	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Small Intestinal Obstruction	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
General disorders Infusion Related Reaction	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Hepatobiliary disorders Biliary Colic	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Hepatobiliary disorders Cholecystitis Acute	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Anal Abscess	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Bacteraemia	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Influenza	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Pelvic Abscess	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.

Other adverse events

Additional Information

Senior Vice President, Global Clinical Development

Merck Sharp & Dohme Corp.

Phone: 1-800-672-6372

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee Prior to submission for publication of results obtained in this study, written permission is required. Draft manuscripts, abstracts \& presentations should be submitted for review \& approval. Schering-Plough Canada will retain the ownership of the data obtained in this study. Authorship of publications resulting from this study should accurately reflect the academic contribution of individuals to the design and implementation of the study, analysis of the data and preparation of the manuscript.
Publication restrictions are in place

Restriction type: OTHER

Measure	Infliximab 5 mg/kg Then Not Randomized n=92 participants at risk Infliximab 5 mg/kg IV at weeks 0, 2 and 6 during the induction phase as well as every 8 weeks during the observational phase. Participants who were further randomized into the interventional phase are not included in this reporting group; therefore, of the 100 enrolled participants, 92 participants were included in this safety reporting group.	Infliximab 5 mg/kg Then Randomized n=8 participants at risk Infliximab 5 mg/kg IV at weeks 0, 2 and 6 during the induction phase as well as every 8 weeks during the observational phase. Participants were then randomized to receive 5 mg/kg every 6 weeks (shortened interval group) or 7 mg/kg every 8 weeks (increased dose group) at entry into the interventional phase. This reporting group included 3 participants randomized into the shortened interval group and 5 participants randomized into the increased dose group.
Gastrointestinal disorders Abdominal Pain	7.6% 7/92 • Number of events 11 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Abdominal Tenderness	4.3% 4/92 • Number of events 4 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Anal Fissure	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Constipation	2.2% 2/92 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Crohn's Disease	5.4% 5/92 • Number of events 6 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	25.0% 2/8 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Gastrointestinal disorders Nausea	9.8% 9/92 • Number of events 11 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
General disorders Discomfort	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
General disorders Fatigue	7.6% 7/92 • Number of events 7 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
General disorders Pyrexia	2.2% 2/92 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Clostridium Difficile Colitis	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Ear Infection	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Nasopharyngitis	10.9% 10/92 • Number of events 11 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Oral Candidiasis	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Tooth Abscess	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	25.0% 2/8 • Number of events 2 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Tooth Infection	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Infections and infestations Vulvovaginal Candidiasis	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Musculoskeletal and connective tissue disorders Arthralgia	6.5% 6/92 • Number of events 6 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Musculoskeletal and connective tissue disorders Musculoskeletal Discomfort	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Musculoskeletal and connective tissue disorders Tendonitis	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Nervous system disorders Headache	10.9% 10/92 • Number of events 14 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Psychiatric disorders Agitation	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Psychiatric disorders Paranoia	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Respiratory, thoracic and mediastinal disorders Oropharyngeal Pain	1.1% 1/92 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Skin and subcutaneous tissue disorders Pruritus	5.4% 5/92 • Number of events 7 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Skin and subcutaneous tissue disorders Psoriasis	0.00% 0/92 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	12.5% 1/8 • Number of events 1 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.
Skin and subcutaneous tissue disorders Rash	5.4% 5/92 • Number of events 5 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.	0.00% 0/8 Enrolled Analysis population (ENR). The ENR population comprised all participants enrolled into the Induction Phase of the protocol and were included in the safety population.