Entre el contexto escolar y el rol familiar en el desarrollo del pensamiento crítico de los

Figure 4presents the Consolidated Standards of Reporting Trials (CONSORT) diagram of participant flow through the trial. In total, 548 patients were reported as having been assessed for eligibility and, of these, 200 (36.5%) provided written informed consent and were randomised into the trial. Of the 348 patients who were reported as having been assessed for the trial but who were not randomised, 177 of these were from a single centre which used a very broad screening process which was inconsistent with other centres. The majority of patients were excluded owing to being clinically ineligible (n=228, 65.5%). Again, this is biased towards the single centre which assessed 172 of these patients as being ineligible as they did not meet key eligibility criteria such as having had no prior therapy for CLL. If this centre is excluded from the screening data, a total of 371 patients were reported as having been assessed for eligibility with 56 (15.1%) being excluded owing to clinical ineligibility. A total of 100 participants were randomised to the FCR control arm and 100 to the FCM-miniR intervention arm.

In the FCR arm, all but two participants received their allocated treatment (n=98, 98.0%). One participant was ineligible (owing to prior therapy for CLL) and went on to receive FCR off trial. The other participant withdrew from the trial on the advice of the treating clinician as they had a 17p deletion and were treated with a more‘appropriate regime’off trial. In the FCM-miniR arm, 79 participants (79.0%) received their allocated intervention throughout the trial, with 21 participants transferring over to receive treatment with FCR as a result of the interim analysis, two from their first cycle of treatment.

A total of nine participants (4.5%) withdrew their consent for the trial (five in the FCR arm and four in the FCM-miniR arm).Table 5summarises the number of participants who withdrew consent from the trial, the type of withdrawal and reason for withdrawal. Two participants withdrew their consent for further trial

Analysis populations ITT (n = 92)

• Excluded from ITT analysis, n = 8

• Missing primary end point data, n = 8

PP (n = 91)

• Excluded from PP analysis, n = 9

• Missing primary end point data, n = 8a

• Breach of eligibility criteria (prior therapy for CLL) and did not receive any FCR, n = 1

• Did not receive any FCR, n = 1a

Safety population (n = 100)

• Excludes two FCR participants who failed to receive any treatment

• Includes two FCM-miniR participants who received FCR from cycle 1

Analysis populations ITT (n = 75)

• Excluded from ITT analysis, n = 25

• Missing primary end point data, n = 5b

• Received FCR, n = 21b

PP (n = 75)

• Excluded from PP analysis, n = 25

• Missing primary end point data, n = 5b

• Received FCR, n = 21b

Safety population (n = 98)

• FCM-miniR, n = 79

• FCM-miniR/FCR, n = 19

Assessed for eligibility (n = 548)

Excluded (n = 348)

• Patient clinically ineligible, n = 228

• Patient did not wish to participate,n = 39

• Patient too ill to participate, n = 4

• Other reason, n = 77

Withdrawn consent from trial (n = 5)

• From trial treatment only, n = 1

• From trial treatment and follow-up data collection, n = 4

Post-randomisation ineligibility (n = 2)

• Prior therapy for CLL, n = 1

• Active or prior hepatitis B or C, n = 1

Lost to follow-up: missing primary end point data (n = 8)

• Missing trephine sample, n = 6

• Withdrew from follow-up data collection prior to assessment of primary end point, n = 2

Allocated to FCR (n = 100)

• Received FCR throughout the trial, n = 98

Did not receive any FCR (n = 2)

• Clinical decision owing to 17p deletion, n = 1

• Breach of eligibility criteria, prior therapy for CLL, n = 1

Withdrawn consent from trial (n = 4)

• From trial treatment only, n = 1

• From trial treatment and follow-up data collection, n = 2

• From follow-up data collection only, n = 1

Post-randomisation ineligibility (n = 0)

Lost to follow-up: missing primary end point data (n = 5)

• Missing trephine sample, n = 4

• Unable to assess owing to insufficient clinical evaluations performed at 3-month post-treatment visit, n = 1

Allocated to FCM-miniR (n = 100)

• Received FCM-miniR throughout the trial, n = 79

• Commenced FCM-miniR but transferred over to FCR as a result of the interim analysis, n = 19

Did not receive any FCM-miniR (n = 2)

• Received FCR from cycle 1 as a result of the interim analysis, n = 2

Randomised (n = 200)

FIGURE 4 Consolidated Standards of Reporting Trials diagram. a, One participant did not receive any FCR and also had missing primary end point data and is therefore recorded twice; and b, one participant received FCR and had missing primary end point data and is therefore recorded twice. Reproduced from Howardet al.1_{with permission.}

STATISTICAL TRIAL RESULTS

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treatment only (one each in the FCR and FCM-miniR arms). Six participants withdrew their consent from further trial treatment and follow-up data collection (four in the FCR arm and two in the FCM-miniR), of which one ineligible participant in the FCR arm did not receive any trial treatment. Primary end point data are available for the two FCM-miniR participants, but all participants in the FCR arm who withdrew from follow-up did so prior to the assessment of the primary end point. One participant in the FCM-miniR arm withdrew their consent for further follow-up data collection only after the assessment of the primary end point, having received all six cycles of treatment.

Three participants in the FCM-miniR arm withdrew because they were unwilling to continue with trial treatment as a result of either toxicity or being too unwell. In the FCR arm, one participant withdrew owing to non- response to treatment, another participant felt that‘Not enough information was given regarding neutropenic sepsis’and that their‘GCSF injections were delayed due to the trial’(categorised as‘Other reason’inTable 5). The median time from randomisation to withdrawal was 2.0 months (range: 0.4–20.7 months) with a shorter median time to withdrawal in the FCR arm (1.8 months) compared with the FCM-miniR arm (8.1 months). Two participants in the FCR arm were found to be ineligible for the trial post randomisation. One participant had received prior therapy for CLL; they received FCR off-trial and continued to be followed up as per the protocol and therefore had available primary end point data within the definition of the ITT population, although they were excluded from the PP population. The second participant had been previously infected with hepatitis B; they continued on the trial under the approval of the Chief Investigator, with the justification that the participant had‘antibodies but no infection’and, therefore, the eligibility deviation was felt to be minor. They received all six cycles of treatment and were followed up for their primary end point.

TABLE 5 Participant withdrawals

Participant withdrawal details

FCR (n₌100) FCM-miniR (n₌100) Total (n₌200) Participant withdrawn,n(%) 5 (5.0) 4 (4.0) 9 (4.5) Type of withdrawal,n(%)

Withdrawn from trial treatment only 1 (1.0) 1 (1.0) 2 (1.0)

Withdrawn from trial treatment and follow-up data collection 4 (4.0) 2 (2.0) 6 (3.0) Withdrawn from follow-up data collection only 0 (0.0) 1 (1.0) 1 (0.5)

Reason for withdrawal

Unwilling to continue with treatment, owing to toxicity 0 (0.0) 2 (2.0) 2 (1.0) Unwilling to continue with treatment, owing to being too unwell 0 (0.0) 1 (1.0) 1 (0.5)

Unwilling to continue with treatment 1 (1.0) 0 (0.0) 1 (0.5)

Unwilling to continue with visits 1 (1.0) 1 (1.0) 2 (1.0)

Non-response to treatment 1 (1.0) 0 (0.0) 1 (0.5)

Clinician decision 1 (1.0) 0 (0.0) 1 (0.5)

Other reason 1 (1.0) 0 (0.0) 1 (0.5)

Trial duration (months) from randomisation to withdrawal

Mean (SD) 2.2 (2.0) 9.6 (8.8) 5.4 (6.8)

Median (range) 1.8 (0.4_–5.7) 8.1 (1.4_–20.7) 2.0 (0.4_–20.7)

N 5 4 9

A total of 13 participants (6.5%) were lost to follow-up and were classed as participants with missing primary end point data, with a similar proportion in each treatment arm (n=8, 8.0% FCR;n=5, 5.0% FCM-miniR). Ten participants (six in the FCR arm and four in the FCM-miniR arm) had a missing trephine sample at 3 months post treatment, which is required to confirm a CR. Four participants (one in the FCR arm and three in the FCM-miniR arm) missed their 3-month post-treatment visit, and one FCM-miniR participant failed to have sufficient clinical evaluations performed. Four participants in the FCR arm withdrew from further follow-up prior to their assessment of response; however, two did so owing to toxicity and non-response to treatment and were therefore included in the ITT analysis as non-responders. For further information on the reasons for missing trephine samples, missed clinic visits, withdrawals and how participants have been handled in the analysis, seeFinal analysis: primary end point.

Overall, 167 participants (83.5%) were included in the ITT analysis, with a higher proportion coming from the FCR arm (n=92, 92.0%) than the FCM-miniR arm (n=75, 75.0%). Participants were excluded from both trial arms owing to missing primary end point data (n=13) and a further 21 participants were excluded from the FCM-miniR arm as a result of receiving treatment with FCR following the closure of the FCM-miniR arm. The PP population was similar to that of the ITT, with an additional participant excluded from the FCR arm owing to breaching the eligibility criteria and not receiving any of their randomised treatment. The participant who had previously been infected with hepatitis B was not excluded from the PP population as this was not classed as a major protocol violation.