Relapsing Multiple Sclerosis (RMS)
Conditions
Keywords
Relapsing Multiple Sclerosis (RMS), Fingolimod, Adult, Pediatric, China
Brief summary
The main purpose of this study was to assess the efficacy and safety of 0.5mg Fingolimod (Gilenya) in Chinese patients with relapsing multiple sclerosis (RMS)
Detailed description
This was a 24-month, open-label, multicenter, interventional, single-arm study to collect efficacy and, safety of oral fingolimod 0.5 mg/day in approximately 100 relapsing multiple sclerosis (RMS) participants in China. The study consisted of three Phases: * Screening (up to 1 month): After signing informed consent, participants entered a Screening Phase to determine eligibility according to inclusion and exclusion criteria. * Treatment Period (24 months): On visit Day 1, all eligibility criteria were confirmed, including a pre-dose ECG and vital signs. The first dose of study drug was taken in the clinic on Day 1 and the participant was monitored for 6 hours after the first dose administration before discharge. Participants returned to site for evaluation at month 1 and then every three months until the end of treatment up to 24 months. * Follow Up (2 months): Subjects who completed Treatment Period or discontinued from treatment returned for the Follow-up visit 2 months after the last dose of study drug.
Interventions
DRUGFingolimod 0.5mg
Subjects received fingolimod 0.5mg capsule QD up to month 24
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
10 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Participant 10 to 17 years old inclusive with weight \> 40kg. * Participant 18 to 65 years old inclusive; * Participants with relapsing multiple sclerosis * Participants never used fingolimod before enrollment * Subjects with Expanded Disability Status Scale (EDSS) score of 0 - 6.0 (inclusive) at Screening
Exclusion criteria
* Participants with certain cardiovascular conditions and/or findings in the screening ECG. * Diagnosis of macular edema during screening visit. * Increased risk for opportunistic infections * Participants with known active malignancies. * Participants who have been treated with teriflunomide within 3.5 months prior to baseline, except if active washout. * Participants with severe active infections, active chronic infection. * Participants with severe liver impairment. * Pregnant confirmed by a positive pregnancy test or nursing (lactating) women.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Adjusted Annualized Relapse Rate (ARR) in Adult Group | Baseline to Month 24 | A confirmed relapse is any relapse that is accompanied by an increase of at least 0.5 on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS) as confirmed by the treating physician. The adjusted annualized relapse rate (ARR) was estimated by a negative binomial regression model with log-link function, the cumulative number of confirmed MS relapses per subject as the response variable, number of relapses in the previous two years before enrollment and baseline EDSS as continuous covariates. Natural log of time on study in years was used as the offset variable to account for the varying lengths of subjects' time in the study. The adjusted ARR (i.e.model-based estimate adjusted for covariates) and the corresponding 95% confidence interval were obtained. As per SAP this analysis was only performed for the Adult group. Descriptive data is presented in subsequent OMs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Annualized Rate of the Number of New or Newly Enlarged T2 Lesions | Baseline to end of treatment (up to Month 24) | Obtained from fitting a negative binomial regression model with log-link function, the total number of new or newly enlarged T2 lesions during the treatment period (per participant) as the response variable. The model included baseline age and volume of T2 lesions at baseline as continuous covariates. Natural log of time from screening scan in years was used as the offset. Baseline is defined as the last non-missing assessment obtained prior to the first administration of study drug. As per SAP this analysis was only performed for the Adult group. |
| Change From Baseline in Number of New or Newly Enlarged T2 Lesions | Baseline up to Month 24 | Number of new/newly enlarged T2 lesions since baseline as measured by MRI |
| Change From Baseline in T2 Lesion Volume | Baseline up to Month 24 | T2 lesion volume as measured by MRI and calculated as post-baseline value - baseline value |
| Number of Gd-enhancing T1 Lesions Per Scan in Adult Group | Baseline up to Month 24 | Obtained from fitting a negative binomial regression model with log-link function, the total number of Gd-enhancing T1 lesions during the treatment period (per patient) as the response variable. The model included baseline age and number of Gd-enhancing T1 lesions at baseline as continuous covariates. Natural log of the number of MRI scans was used as the offset. MRI scans were performed at baseline, month 12 and month 24 and End of treatment for participants that discontinued treatment. Unscheduled MRIs could be performed at the investigator's judgement. As per SAP this analysis was only performed for the Adult group. |
| Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | From first dose of study treatment to 45 days after last study dose up to aproximately 25.5 months | An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject after providing written informed consent for participation in the study. For reporting purposes, the main focus was on treatment emergent adverse event (TEAE), defined as any AE which started on or after the day of first dose of study medication or events present prior to the start of treatment but increased in severity. |
| Change From Baseline in Gd-enhancing T1 Lesion Volume | Baseline up to Month 24 | Gd-enhancing T1 lesion volume as measured by MRI and calculated as post-baseline value - baseline value |
| Number of T1 Hypo-intense Lesions | Baseline up to Month 24 | Number of T1 hypo-intense lesions as measured by MRI |
| Change From Baseline in T1 Hypo-intense Lesion Volume | Baseline up to Month 24 | T1 hypo-intense lesions as measured by MRI and calculated as post-baseline value - baseline value |
| Number of Gd-enhancing T1 Lesions | Baseline up to Month 24 | Number of Gd-enhancing T1 lesions as measured by MRI |
Countries
China
Participant flow
Recruitment details
Participants were enrolled at 13 sites in China
Pre-assignment details
There were up to 30 days of screening period (day -30 to -1) before first treatment (day 1).
Participants by arm
| Arm | Count |
|---|---|
| Fingolimod (< 18 Years) Fingolimod 0.5 mg capsule taken orally once daily in participants under 18 years old | 11 |
| Fingolimod > 18 Years Fingolimod 0.5 mg capsule taken orally once daily in participants 18 years old or over | 87 |
| Total | 98 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Physician Decision | 0 | 2 |
| Overall Study | Subject decision | 1 | 7 |
Baseline characteristics
| Characteristic | Fingolimod (< 18 Years) | Fingolimod > 18 Years | Total |
|---|---|---|---|
| Age categorical Adolescents 12-17 years | 9 Participants | 0 Participants | 9 Participants |
| Age categorical Adults 18-64 years | 0 Participants | 87 Participants | 87 Participants |
| Age categorical Children 2-11 years | 2 Participants | 0 Participants | 2 Participants |
| Age, Continuous | 12.8 years STANDARD_DEVIATION 1.6 | 32.3 years STANDARD_DEVIATION 9.11 | 30.1 years STANDARD_DEVIATION 10.58 |
| Number of relapses in 12 to 24 months prior to screening | 0.8 relapses/year STANDARD_DEVIATION 1.25 | 0.7 relapses/year STANDARD_DEVIATION 0.84 | 0.7 relapses/year STANDARD_DEVIATION 0.89 |
| Number of relapses in the last 12 months prior to screening | 1.7 relapses/year STANDARD_DEVIATION 1.27 | 1.2 relapses/year STANDARD_DEVIATION 0.47 | 1.3 relapses/year STANDARD_DEVIATION 0.62 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 11 Participants | 87 Participants | 98 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 3 Participants | 51 Participants | 54 Participants |
| Sex: Female, Male Male | 8 Participants | 36 Participants | 44 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 11 | 0 / 87 | 0 / 98 |
| other Total, other adverse events | 11 / 11 | 85 / 87 | 96 / 98 |
| serious Total, serious adverse events | 3 / 11 | 12 / 87 | 15 / 98 |
Outcome results
Primary
Adjusted Annualized Relapse Rate (ARR) in Adult Group
A confirmed relapse is any relapse that is accompanied by an increase of at least 0.5 on the EDSS or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS) as confirmed by the treating physician. The adjusted annualized relapse rate (ARR) was estimated by a negative binomial regression model with log-link function, the cumulative number of confirmed MS relapses per subject as the response variable, number of relapses in the previous two years before enrollment and baseline EDSS as continuous covariates. Natural log of time on study in years was used as the offset variable to account for the varying lengths of subjects' time in the study. The adjusted ARR (i.e.model-based estimate adjusted for covariates) and the corresponding 95% confidence interval were obtained. As per SAP this analysis was only performed for the Adult group. Descriptive data is presented in subsequent OMs.
Time frame: Baseline to Month 24
Population: Adult participants in the Full Analysis Set (FAS). FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod (< 18 Years) | Adjusted Annualized Relapse Rate (ARR) in Adult Group | 0.018 relapses per participant-year |
Secondary
Annualized Rate of the Number of New or Newly Enlarged T2 Lesions
Obtained from fitting a negative binomial regression model with log-link function, the total number of new or newly enlarged T2 lesions during the treatment period (per participant) as the response variable. The model included baseline age and volume of T2 lesions at baseline as continuous covariates. Natural log of time from screening scan in years was used as the offset. Baseline is defined as the last non-missing assessment obtained prior to the first administration of study drug. As per SAP this analysis was only performed for the Adult group.
Time frame: Baseline to end of treatment (up to Month 24)
Population: Adult participants in the Full Analysis Set (FAS) with available data for the outcome measure.. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod (< 18 Years) | Annualized Rate of the Number of New or Newly Enlarged T2 Lesions | 1.316 Lesions per participant-year |
Secondary
Change From Baseline in Gd-enhancing T1 Lesion Volume
Gd-enhancing T1 lesion volume as measured by MRI and calculated as post-baseline value - baseline value
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with non-missing, non-zero baseline and post-baseline values for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fingolimod (< 18 Years) | Change From Baseline in Gd-enhancing T1 Lesion Volume | 12 months | -56.0 microliters |
| Fingolimod (< 18 Years) | Change From Baseline in Gd-enhancing T1 Lesion Volume | 24 months | -56.0 microliters |
| Fingolimod > 18 Years | Change From Baseline in Gd-enhancing T1 Lesion Volume | 12 months | 0.00 microliters |
| Fingolimod > 18 Years | Change From Baseline in Gd-enhancing T1 Lesion Volume | 24 months | 0.00 microliters |
Secondary
Change From Baseline in Number of New or Newly Enlarged T2 Lesions
Number of new/newly enlarged T2 lesions since baseline as measured by MRI
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with available data for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod (< 18 Years) | Change From Baseline in Number of New or Newly Enlarged T2 Lesions | 12 months | 1.8 new / newly enlarged T2 lesions | Standard Deviation 1.93 |
| Fingolimod (< 18 Years) | Change From Baseline in Number of New or Newly Enlarged T2 Lesions | 24 months | 2.1 new / newly enlarged T2 lesions | Standard Deviation 2.18 |
| Fingolimod > 18 Years | Change From Baseline in Number of New or Newly Enlarged T2 Lesions | 12 months | 1.8 new / newly enlarged T2 lesions | Standard Deviation 4.18 |
| Fingolimod > 18 Years | Change From Baseline in Number of New or Newly Enlarged T2 Lesions | 24 months | 2.4 new / newly enlarged T2 lesions | Standard Deviation 4.84 |
Secondary
Change From Baseline in T1 Hypo-intense Lesion Volume
T1 hypo-intense lesions as measured by MRI and calculated as post-baseline value - baseline value
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with non-missing, non-zero baseline and post-baseline values for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fingolimod (< 18 Years) | Change From Baseline in T1 Hypo-intense Lesion Volume | 12 months | -77.500 microliters |
| Fingolimod (< 18 Years) | Change From Baseline in T1 Hypo-intense Lesion Volume | 24 months | -641.415 microliters |
| Fingolimod > 18 Years | Change From Baseline in T1 Hypo-intense Lesion Volume | 12 months | 44.000 microliters |
| Fingolimod > 18 Years | Change From Baseline in T1 Hypo-intense Lesion Volume | 24 months | 187.100 microliters |
Secondary
Change From Baseline in T2 Lesion Volume
T2 lesion volume as measured by MRI and calculated as post-baseline value - baseline value
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with non-missing, non-zero baseline and post-baseline values for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Fingolimod (< 18 Years) | Change From Baseline in T2 Lesion Volume | 12 months | 0.6140 milliliters |
| Fingolimod (< 18 Years) | Change From Baseline in T2 Lesion Volume | 24 months | -1.6736 milliliters |
| Fingolimod > 18 Years | Change From Baseline in T2 Lesion Volume | 12 months | 0.3930 milliliters |
| Fingolimod > 18 Years | Change From Baseline in T2 Lesion Volume | 24 months | 0.4065 milliliters |
Secondary
Number of Gd-enhancing T1 Lesions
Number of Gd-enhancing T1 lesions as measured by MRI
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with available data for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod (< 18 Years) | Number of Gd-enhancing T1 Lesions | 12 months | 0.4 T1 lesions | Standard Deviation 0.7 |
| Fingolimod (< 18 Years) | Number of Gd-enhancing T1 Lesions | 24 months | 0 T1 lesions | Standard Deviation 0 |
| Fingolimod > 18 Years | Number of Gd-enhancing T1 Lesions | 12 months | 0.4 T1 lesions | Standard Deviation 0.84 |
| Fingolimod > 18 Years | Number of Gd-enhancing T1 Lesions | 24 months | 0.4 T1 lesions | Standard Deviation 1.83 |
Secondary
Number of Gd-enhancing T1 Lesions Per Scan in Adult Group
Obtained from fitting a negative binomial regression model with log-link function, the total number of Gd-enhancing T1 lesions during the treatment period (per patient) as the response variable. The model included baseline age and number of Gd-enhancing T1 lesions at baseline as continuous covariates. Natural log of the number of MRI scans was used as the offset. MRI scans were performed at baseline, month 12 and month 24 and End of treatment for participants that discontinued treatment. Unscheduled MRIs could be performed at the investigator's judgement. As per SAP this analysis was only performed for the Adult group.
Time frame: Baseline up to Month 24
Population: Adult participants in the Full Analysis Set (FAS) with available data for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Fingolimod (< 18 Years) | Number of Gd-enhancing T1 Lesions Per Scan in Adult Group | 0.376 Lesions per participant per scan |
Secondary
Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE)
An adverse event (AE) is any untoward medical occurrence in a clinical investigation subject after providing written informed consent for participation in the study. For reporting purposes, the main focus was on treatment emergent adverse event (TEAE), defined as any AE which started on or after the day of first dose of study medication or events present prior to the start of treatment but increased in severity.
Time frame: From first dose of study treatment to 45 days after last study dose up to aproximately 25.5 months
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse events (AEs) | 11 Participants |
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Study treatment related AEs | 10 Participants |
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Serious adverse events (SAEs) | 3 Participants |
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to interruption of study treatment | 3 Participants |
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to study discontinuation | 1 Participants |
| Fingolimod (< 18 Years) | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to death | 0 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to study discontinuation | 5 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Adverse events (AEs) | 86 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to interruption of study treatment | 11 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Study treatment related AEs | 81 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | AEs leading to death | 0 Participants |
| Fingolimod > 18 Years | Number of Participants With Treatment Emergent Adverse Events (AE) and Serious Adverse Events (SAE) | Serious adverse events (SAEs) | 12 Participants |
Secondary
Number of T1 Hypo-intense Lesions
Number of T1 hypo-intense lesions as measured by MRI
Time frame: Baseline up to Month 24
Population: Participants in the Full Analysis Set (FAS) with available data for the outcome measure. FAS: all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod (< 18 Years) | Number of T1 Hypo-intense Lesions | 12 months | 14.6 T1 hypo-intense lesions | Standard Deviation 12.97 |
| Fingolimod (< 18 Years) | Number of T1 Hypo-intense Lesions | 24 months | 13.4 T1 hypo-intense lesions | Standard Deviation 10.86 |
| Fingolimod > 18 Years | Number of T1 Hypo-intense Lesions | 12 months | 17.0 T1 hypo-intense lesions | Standard Deviation 13.62 |
| Fingolimod > 18 Years | Number of T1 Hypo-intense Lesions | 24 months | 16.7 T1 hypo-intense lesions | Standard Deviation 13.27 |
Post Hoc
Participant Based Annualized Relapse Rate (ARR)
A relapse is an appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event which is present for at least 24 hours in the absence of fever or infection. A relapse is confirmed by the treating physician when it is accompanied by an increase of at least 0.5 on the Expanded Disability Status Scale (EDSS) or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). Participant-based ARR was calculated by taking the total number of relapses observed for a participant divided by the total number of days in study of that participant and multiplied by 365.25.
Time frame: Baseline to Month 24
Population: Full Analysis Set (FAS): all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Fingolimod (< 18 Years) | Participant Based Annualized Relapse Rate (ARR) | All relapses - Participant based | 0.1952 relapses per participant-year | Standard Deviation 0.50314 |
| Fingolimod (< 18 Years) | Participant Based Annualized Relapse Rate (ARR) | Confirmed relapses - Participant based | 0.0460 relapses per participant-year | Standard Deviation 0.15253 |
| Fingolimod > 18 Years | Participant Based Annualized Relapse Rate (ARR) | All relapses - Participant based | 0.0969 relapses per participant-year | Standard Deviation 0.50002 |
| Fingolimod > 18 Years | Participant Based Annualized Relapse Rate (ARR) | Confirmed relapses - Participant based | 0.0372 relapses per participant-year | Standard Deviation 0.24424 |
Post Hoc
Time Based Annualized Relapse Rate (ARR)
A relapse is an appearance of a new neurological abnormality or worsening of previously stable or improving pre-existing neurological abnormality, separated by at least 30 days from onset of a preceding clinical demyelinating event which is present for at least 24 hours in the absence of fever or infection. A relapse is confirmed by the treating physician when it is accompanied by an increase of at least 0.5 on the Expanded Disability Status Scale (EDSS) or an increase of 1 point on two different Functional Systems (FS) of the EDSS or 2 points on one of the FS (excluding Bowel/Bladder or Cerebral FS). Time-based ARR was calculated by taking the total number of relapses observed for all subjects within an age group divided by the total number of days in study of all subjects within the group and multiplied by 365.25 days.
Time frame: Baseline to Month 24
Population: Full Analysis Set (FAS): all participants who had signed the Informed Consent and who had received at least one dose of study treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Fingolimod (< 18 Years) | Time Based Annualized Relapse Rate (ARR) | All relapses - Time based | 0.161 relapses per participant-year |
| Fingolimod (< 18 Years) | Time Based Annualized Relapse Rate (ARR) | Confirmed relapses - Time based | 0.054 relapses per participant-year |
| Fingolimod > 18 Years | Time Based Annualized Relapse Rate (ARR) | All relapses - Time based | 0.065 relapses per participant-year |
| Fingolimod > 18 Years | Time Based Annualized Relapse Rate (ARR) | Confirmed relapses - Time based | 0.019 relapses per participant-year |