Crohn's Disease
Conditions
Keywords
Active Crohn's disease, Anti-TNF Refractory, Immunosuppressant Refractory
Brief summary
This study provides open-label drug to eligible patients who have completed a prior study of PF-00547659. The primary endpoint for this study is long-term safety.
Detailed description
The rationale for conducting this open-label extension (OLE) study is primarily to evaluate long term safety of PF 00547659. This protocol also provides the opportunity for continued treatment for subjects responding to treatment from the feeder study. It also provides an opportunity for initial treatment for subjects randomized to placebo in the feeder study. This is a multi center Phase 2, open label, safety extension study for feeder studies which evaluate PF 00546759 in subjects with moderate to severe Crohn's disease. Subjects eligible for this study will have completed the 12 week double blind induction period in study A7281006 and will be stratified by responders or non responders based on change in CDAI in that study, without unblinding treatment assignment from study A7281006. Additionally, subjects who have completed study A7281008 with a clinical response, as defined by that protocol, will also be eligible for this study and treated as responders. All subjects entering this study must have discontinued immunosuppressant therapy. Subjects entering this study will be given a 75 mg SC dose at baseline and then every 4 weeks through Week 72. After the active treatment period, the subjects will enter a 24 month follow up period including 6 monthly visits followed by 18 month extended contact (every 6 month telephone contacts). At Week 96, subjects will undergo an End of Study visit but will continue the every 6 month telephone contacts until Week 168.
Interventions
DRUGPF-00547659
75 mg SC once monthly for 72 weeks. Subjects may escalate to 225 mg or de-escalate to 22.5 mg one time.
Sponsors
Shire
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subjects between 18 and 76 years of age. * Subjects previously enrolled in study A7281006 who have completed the blinded 84 day (12 week) induction period or in study A7281008 who have completed Week 12 and have demonstrated a clinical response as defined by that protocol.
Exclusion criteria
* Subjects that have completed Day 84 (Week 12) of a PF-00547659 study but have experienced serious event(s) related to the investigational product, an unstable medical condition, or any other reason, in the opinion of the investigator, would hinder entry or participation in this study. * Subjects who are taking any dose of azathioprine, 6-mercaptopurine or methotrexate.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With On-Treatment Adverse Events (AEs), AEs Led to Withdrawal, and Serious Adverse Events (SAEs) | From start of study treatment up to Week 72 (Treatment Period) | AEs included adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, clinically significant changes in physical examination findings and abnormal objective test findings (ECG, laboratory). An SAE was defined as any AE at any dose that resulted in death; was life threatening (immediate risk of death); required in-subject hospitalization or prolongation of existing hospitalization; resulted in a persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); or resulted in congenital anomaly/birth defect. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Positive Anti-Drug (PF-00547659) Antibodies | Baseline up to Week 96 | Positive Anti-Drug Antibodies result was defined as ADA titre value greater than or equal to (\>=) 4.64 at at least one of the time points. |
| Serum Trough Concentrations of PF-00547659 Versus Time | Week 4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,84,88,92,96 | Serum trough concentrations of PF-00547659 were analyzed using population Pharmacokinetic (PK) methodology. |
Countries
Austria, Belgium, Canada, France, Germany, Japan, Netherlands, Norway, Poland, Serbia, Slovakia, South Africa, South Korea, Spain, United States
Participant flow
Recruitment details
The study was conducted at 81 centers in Austria, Belgium, Canada, France, Germany, Japan, Netherlands, Norway, Poland, Republic of Korea, Serbia, Slovakia, South Africa, Spain and United States between 22 July 2011 (first participant first visit) and 27 July 2016 (last participant last visit).
Pre-assignment details
A total of 268 participants (225 participants from Feeder Study A7281006 \[NCT01276509\] and 43 participants from Feeder Study A7281008 \[NCT01387594\]) were enrolled and overall 149 participants completed the study.
Participants by arm
| Arm | Count |
|---|---|
| PF-00547659 75 mg Participants received PF-00547659 75 mg subcutaneous injection once in every 4 weeks through Week 72. One time dose escalation to 225 mg subcutaneous injection was allowed after 8 weeks of the study for the participants who experienced clinical deterioration or unacceptably low level of response to study drug. One time dose de-escalation to 22.5 mg subcutaneous injection due to intolerance or AEs was also allowed after the investigator carefully assessed the status of the participant. | 268 |
| Total | 268 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event(Not Related to Study Drug) | 18 |
| Overall Study | Adverse Event(Related to Study Drug) | 8 |
| Overall Study | Death | 2 |
| Overall Study | Insufficient Clinical Response | 22 |
| Overall Study | Lost to Follow-up | 12 |
| Overall Study | Other (Unspecified) | 7 |
| Overall Study | Protocol Violation | 2 |
| Overall Study | Withdrawal by Subject | 47 |
| Overall Study | Withdrawn Due to Pregnancy | 1 |
Baseline characteristics
| Characteristic | PF-00547659 75 mg |
|---|---|
| Age, Continuous | 36.5 year STANDARD_DEVIATION 11.7 |
| Sex: Female, Male Female | 151 Participants |
| Sex: Female, Male Male | 117 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 2 / 268 |
| other Total, other adverse events | 206 / 268 |
| serious Total, serious adverse events | 118 / 268 |
Outcome results
Primary
Number of Participants With On-Treatment Adverse Events (AEs), AEs Led to Withdrawal, and Serious Adverse Events (SAEs)
AEs included adverse drug reactions, illnesses with onset during the study, exacerbation of previous illnesses, clinically significant changes in physical examination findings and abnormal objective test findings (ECG, laboratory). An SAE was defined as any AE at any dose that resulted in death; was life threatening (immediate risk of death); required in-subject hospitalization or prolongation of existing hospitalization; resulted in a persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions); or resulted in congenital anomaly/birth defect.
Time frame: From start of study treatment up to Week 72 (Treatment Period)
Population: The modified intent-to-treat (mITT) population included all enrolled participants who received at least 1 dose of investigational product.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| PF-00547659 75 mg | Number of Participants With On-Treatment Adverse Events (AEs), AEs Led to Withdrawal, and Serious Adverse Events (SAEs) | Participants With AEs | 249 Participants |
| PF-00547659 75 mg | Number of Participants With On-Treatment Adverse Events (AEs), AEs Led to Withdrawal, and Serious Adverse Events (SAEs) | Participants With AEs Led to Withdrawal | 53 Participants |
| PF-00547659 75 mg | Number of Participants With On-Treatment Adverse Events (AEs), AEs Led to Withdrawal, and Serious Adverse Events (SAEs) | Participants With SAEs | 80 Participants |
Secondary
Number of Participants With Positive Anti-Drug (PF-00547659) Antibodies
Positive Anti-Drug Antibodies result was defined as ADA titre value greater than or equal to (\>=) 4.64 at at least one of the time points.
Time frame: Baseline up to Week 96
Population: The modified intent-to-treat (mITT) population included all enrolled participants who received at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| PF-00547659 75 mg | Number of Participants With Positive Anti-Drug (PF-00547659) Antibodies | 63 Participants |
Secondary
Serum Trough Concentrations of PF-00547659 Versus Time
Serum trough concentrations of PF-00547659 were analyzed using population Pharmacokinetic (PK) methodology.
Time frame: Week 4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,84,88,92,96
Population: PK population included all enrolled participants who received at least 1 dose of investigational product and had data on at least 1 PK concentration.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 4 | 6673 nanogram per milliliter (ng/mL) | Standard Deviation 6634.2 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 8 | 6064 nanogram per milliliter (ng/mL) | Standard Deviation 4455.3 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 12 | 8040 nanogram per milliliter (ng/mL) | Standard Deviation 6293.1 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 16 | 9563 nanogram per milliliter (ng/mL) | Standard Deviation 7285.4 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 20 | 10400 nanogram per milliliter (ng/mL) | Standard Deviation 8438.6 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 24 | 10450 nanogram per milliliter (ng/mL) | Standard Deviation 7934.6 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 28 | 10780 nanogram per milliliter (ng/mL) | Standard Deviation 9211 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 32 | 11920 nanogram per milliliter (ng/mL) | Standard Deviation 10675 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 36 | 12460 nanogram per milliliter (ng/mL) | Standard Deviation 9717.1 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 40 | 12570 nanogram per milliliter (ng/mL) | Standard Deviation 10077 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 44 | 12960 nanogram per milliliter (ng/mL) | Standard Deviation 10999 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 48 | 13170 nanogram per milliliter (ng/mL) | Standard Deviation 11108 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 52 | 13560 nanogram per milliliter (ng/mL) | Standard Deviation 11388 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 56 | 13930 nanogram per milliliter (ng/mL) | Standard Deviation 11191 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 60 | 14130 nanogram per milliliter (ng/mL) | Standard Deviation 11095 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 64 | 14360 nanogram per milliliter (ng/mL) | Standard Deviation 11290 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 68 | 14990 nanogram per milliliter (ng/mL) | Standard Deviation 12883 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 72 | 13910 nanogram per milliliter (ng/mL) | Standard Deviation 10554 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 76 | 10520 nanogram per milliliter (ng/mL) | Standard Deviation 10082 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 80 | 3555 nanogram per milliliter (ng/mL) | Standard Deviation 5339.8 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 84 | 1129 nanogram per milliliter (ng/mL) | Standard Deviation 2634.7 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 88 | 403.8 nanogram per milliliter (ng/mL) | Standard Deviation 1522.6 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 92 | 154.2 nanogram per milliliter (ng/mL) | Standard Deviation 1001.9 |
| PF-00547659 75 mg | Serum Trough Concentrations of PF-00547659 Versus Time | Week 96 | 54.73 nanogram per milliliter (ng/mL) | Standard Deviation 487.07 |