La percepción del pensamiento crítico en las aulas exclusivas

An interim analysis of the short-term efficacy data was performed on the first 103 participants randomised into the study: 51 allocated to the FCR control arm and 52 allocated to the FCM-miniR intervention arm. The results of the interim analysis were presented to the DMEC in September 2012.

The interim analysis was based on all data received and entered into the trial database up to 30 August 2012. Owing to the ongoing nature of the trial, the DMEC was aware that the data on which the interim analysis was based may not have been fully validated and could be subject to change by the time of the final analysis. This report summarises the data as they were reported to the DMEC, even if there were changes to these results prior to the final, clean, analysis data set.

By the time the final participant to be included in the interim analysis had reached their primary end point (i.e. 3 months post treatment), 191 participants out of a target of 206 had been randomised from 32 UK centres. The primary aim of the formal interim analysis was to be able to release information on any potential large differences in efficacy between the treatment arms earlier than would have been the case with the final analysis.

Treatment received

Of the first 103 participants randomised, 72 (69.9%) received all six cycles of treatment, with a higher proportion of participants coming from the FCR arm (n=38, 74.5%) than the FCM-miniR arm (n=34, 65.4%) (Table 16). Thirty-one participants (30.1%) had discontinued treatment early (FCR: 25.5%,n=13; FCM-miniR: 34.6%,n=18).

Table 17summarises the number and proportion of participants experiencing at least one modification to their protocol-defined dose of treatment. A higher proportion of participants in the FCM-miniR arm experienced at least one dose omission, dose reduction and dose delay than in the FCR arm.

TABLE 15 Granulocyte colony-stimulating factor usage by number of treatment cycles received

Number of treatment cycles received

Received GCSF within first three cycles (n₌68),n(%)

Did not receive GCSF within first three cycles (n₌110),n(%) Unknown (n₌20),n(%) Total (n₌198),n(%) 1 0 (0.0) 0 (0.0) 8 (40.0) 8 (4.0) 2 2 (2.9) 0 (0.0) 10 (50.0) 12 (6.1) 3 6 (8.8) 2 (1.8) 1 (5.0) 9 (4.5) 4 5 (7.4) 6 (5.5) 0 (0.0) 11 (5.6) 5 5 (7.4) 12 (10.9) 0 (0.0) 17 (8.6) 6 50 (73.5) 90 (81.8) 1 (5.0) 141 (71.2)

TABLE 16 Treatment details (interim analysis population)

Treatment details FCR (n₌51) FCM-miniR (n₌52) Total (n₌103) Number of treatment cycles received,n(%)

1 0 (0.0) 3 (5.8) 3 (2.9) 2 5 (9.8) 1 (1.9) 6 (5.8) 3 1 (2.0) 2 (3.8) 3 (2.9) 4 3 (5.9) 5 (9.6) 8 (7.8) 5 4 (7.8) 7 (13.5) 11 (10.7) 6 38 (74.5) 34 (65.4) 72 (69.9)

STATISTICAL TRIAL RESULTS

NIHR Journals Library www.journalslibrary.nihr.ac.uk

Efficacy

An independent central assessment of response was carried out in order to assess formally the primary end point data on response to treatment as defined by IWCLL criteria.26_{The interim analysis of the primary} end point data was based on the ITT population, which included participants for whom written informed consent had been received and for which primary end point data were available. A PP analysis was not performed as, out of the first 103 participants, all received at least one cycle of their randomised

treatment. The FCR participant who had been previously infected with hepatitis B was not excluded as this was not classed as a major protocol violation.

Of the 103 participants assessed in the interim analysis, 18 (17.5%) were excluded from the formal analysis of the primary end point, with a slightly higher proportion coming from the FCR arm (FCR:n=10, 19.6%; FCM-miniR:n=8, 15.4%) (Table 18). Fifteen participants had a missing trephine sample (7 FCR; 8 FCM-miniR), which is required by the IWCLL criteria to confirm a CR, with no further evidence that they were definitely not a CR/CRi. Of these, two trephine samples were taken but were inadequate for analysis. Thirteen samples were not taken owing to a sample being missed in error (n=4); a clinician’s decision (n=2); a participant’s decision (n=2); a participant being unwell (n=1); it being too painful/difficult to sample a participant (n=4).

In the FCR arm, two participants withdrew their consent for further trial treatment and follow-up data collection prior to the assessment of the primary end point, and one participant discontinued treatment after their second cycle and was subsequently lost to follow-up.

Table 19presents the number of participants achieving a CR and the difference in response rates between the treatment arms. Overall, 71.8% (n=61) of participants achieved a CR, with a higher proportion in the FCR arm (n=34, 82.9%) than in the FCM-miniR arm (n=27. 61.4%). The difference in the CR rates was 21.6% in favour of the FCR arm, with a 99.5% CI (–48.0% to 4.8%).

TABLE 17 Treatment modifications (interim analysis population)

Treatment modifications FCR (n₌51) FCM-miniR (n₌52) Total (n₌103) Dose modification,n(%)

Dose omission 1 (2.0) 7 (13.5) 8 (7.8)

Dose reduction 15 (29.4) 20 (38.5) 35 (34.0)

Dose delay 23 (45.1) 28 (53.8) 51 (49.5)

TABLE 18 Exclusions from the interim analysis of the primary end point (interim analysis population)

Exclusion FCR (n=51) FCM-miniR (n=52) Total (n=103)

Participants excluded from the primary end point analysis,n(%) 10 (19.6) 8 (15.4) 18 (17.5)

Reasons for exclusion,n(%)

Missing 3-month post-treatment trephine sample 7 (13.7) 8 (15.4) 15 (14.6) Withdrew from further trial treatment and follow-up

data collection

2 (3.9) 0 (0.0) 2 (1.9)

A binary multivariate logistic regression model was used to assess formally the effect of treatment on the proportion of participants achieving a CR at 3 months post treatment, adjusting for the minimisation factors, excluding centre (Table 20). The O’Brien and Fleming32_{alpha spending function was used to adjust} for multiple testing, requiring an alpha level of<0.005 (two-sided) to indicate significance, in order to preserve the alpha for the final analysis.

The OR for achieving a CR in the FCM-miniR arm compared with the FCR arm was 0.32 (99.5% CI: 0.07 to 1.48). With ap-value of 0.037, the difference between the treatment arms in terms of CR rates was not significant at the reduced 0.5% significance level, although it was noted that the experimental treatment was somewhat worse in terms of response.

Of the 103 participants included in the interim analysis, 51.5% (n=53) had undetectable MRD at

3 months post treatment, with a higher proportion of participants in the FCR arm (n=29, 56.9%) than in the FCM-miniR arm (n=24, 46.2%) (Table 21).

TABLE 19 Proportion of participants achieving a CR/CRi at 3 months post treatment (ITT population)

Achievement of the

primary end point FCR (n₌41)

FCM-miniR (n₌44) Total (n₌85) Difference in response rates (FCM_–miniR-FCR) 99.5% CI for difference in response rate Achieved a CR/CRi,n(%) 34 (82.9) 27 (61.4) 61 (71.8) –21.6 –48.0% to 4.8% Did not achieve a CR/CRi,

n(%)

7 (17.1) 17 (38.6) 24 (28.2)

TABLE 20 Multivariate logistic regression analysis for the proportion of participants achieving a CR or CRi at 3 months post treatment, adjusted for the minimisation factors (ITT population)

Parameter df Parameter estimate SE Waldχ2 _Pr>χ2 _{OR (99.5% CI)}

Intercept 1 0.81 0.31 6.86 0.009

Treatment group: FCM-miniR vs. FCR 1 _–0.56 0.27 4.34 0.037 0.32 (0.07 to 1.48)

Sex: female vs. male 1 0.31 0.31 1.02 0.312 1.87 (0.33 to 10.55)

Age group:>65 years vs.≤65 years 1 –0.56 0.28 3.91 0.048 0.32 (0.07 to 1.60) Binet stage: C vs. A progressive or B 1 _–0.42 0.28 2.35 0.125 0.43 (0.09 to 2.02) df, degrees of freedom.

TABLE 21 Proportion of participants achieving MRD negativity at 3 months post treatment (interim analysis population)

MRD assessment FCR (n₌51) FCM-miniR (n₌52) Total (n₌103) Assessment of MRD,n(%)

MRD negative 29 (56.9) 24 (46.2) 53 (51.5)

MRD positive 19 (37.3) 22 (42.3) 41 (39.8)

Unknown, samples not taken 0 (0.0) 5 (9.6) 5 (4.9)

Early death 0 (0.0) 1 (1.9) 1 (1.0)

Withdrew from further trial treatment and follow-up data collection

2 (3.9) 0 (0.0) 2 (1.9)

Lost to follow-up 1 (2.0) 0 (0.0) 1 (1.0)

STATISTICAL TRIAL RESULTS

NIHR Journals Library www.journalslibrary.nihr.ac.uk

Safety and toxicity

A total of 103 SAEs were reported from 60 participants out of the first 103 randomised into the trial. Of the 103 reported SAEs, 44 events (42.7%) were from 26 participants receiving FCR and 59 events (57.3%) were from 34 participants receiving FCM-miniR. The mean number of SAEs reported per participant (1.7) was the same in both treatment arms (Table 22).

Of the 103 SAEs reported, 85 (82.5%) were suspected to be related to trial treatment (51 reported from participants receiving FCM-miniR and 34 reported from participants receiving FCR). One SUSAR was reported from a participant in the FCR arm. The participant received all six cycles of treatment and was diagnosed with a‘squamous cell carcinoma’approximately 4 months after their last cycle of treatment. The event was felt by the Principal Investigator at the site to be related to trial treatment (F, C and R) and unexpected. The majority of SAEs required hospitalisation (n=89, 86.4%); three participants died as a result of their SAE (one in the FCR arm and two in the FCM-miniR arm) (Table 23).

A total of 1469 AEs were reported from 101 participants. A total of 669 events were from 49 participants receiving FCR and 770 events from 52 participants receiving FCM-miniR.

TABLE 22 Number of participants experiencing an SAE and total number of SAEs reported (interim analysis population)

SAE summary FCR (n=51) FCM-miniR (n=52) Total (n=103) Has the participant experienced an SAE?,n(%)

Yes 26 (51.0) 34 (65.4) 60 (58.3)

No 25 (49.0) 18 (34.6) 43 (41.7)

Number of participants with one or more SAE 26 34 60

Number of SAEs reported 44 59 103

Number of SAEs per participant

Mean (SD) 1.7 (1.2) 1.7 (1.1) 1.7 (1.1)

Median (range) 1 (1–5) 1 (1–5) 1 (1–5)

SD, standard deviation.

TABLE 23 Suspected relationship with experimental treatment (interim analysis population)

SAE relationship and seriousness criteria FCR,N(%) FCM-miniR,N(%) Total,N(%)

Relationship to experimental treatment

Suspected, unexpected 1 (2.3) 0 (0.0) 1 (1.0)

Suspected, expected 33 (75.0) 51 (86.4) 84 (81.6)

Not suspected 10 (22.7) 8 (13.6) 18 (17.5)

Total 44 (100) 59 (100.0) 103 (100)

Seriousness criteria (not mutually exclusive)

Participant died as a result of the SAE 1 (2.3) 2 (3.4) 3 (2.9)

Life-threatening 1 (2.3) 3 (5.1) 4 (3.9)

Congenital anomaly/birth defect 0 (0.0) 0 (0.0) 0 (0.0)

Required/prolonged hospitalisation 39 (88.6) 50 (84.7) 89 (86.4)

Persistent or significant disability/incapacity 1 (2.3) 0 (0.0) 1 (1.0) Jeopardised patient/required intervention to

prevent one of the above criteria

6 (13.6) 10 (16.9) 16 (15.5)

Conclusions from the Data Monitoring and Ethics Committee

The difference in the CR rates between the treatment arms (82.9% FCR; 61.4% FCM-miniR), although not statistically significant, was deemed by the DMEC to be clinically relevant. In light of this, and the indication of an increased toxicity rate and increased number of dose omissions and reductions in the FCM-miniR arm, the DMEC recommended that the trial should close the recruitment with immediate effect, and all participants receiving FCM-miniR were recommended to transfer to treatment with FCR for the remainder of their treatment cycles. At the time of trial closure, 200 participants had been recruited into the trial.