Here is the design of a clinical trial:

Official Title: Myeloma XIV: A Phase III Trial to Compare Standard and Frailty-adjusted Induction Therapy With Ixazomib, Lenalidomide and Dexamethasone (IRD) and Maintenance Lenalidomide (R) to Lenalidomide Plus Ixazomib (R+I)

Included conditions:
- Multiple Myeloma

Study Armgroups:
- {'label': 'R1: IRD induction therapy (reactive)', 'type': 'ACTIVE_COMPARATOR', 'description': 'In the reactive arm at Randomisation 1, participants will receive IRD induction therapy with standard up-front dosing, with toxicity assessed at each cycle and doses adjusted in accordance with the guidelines given in the trial protocol.', 'interventionNames': ['Drug: R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - reactive arm']}
- {'label': 'R1: IRD induction therapy (adaptive)', 'type': 'EXPERIMENTAL', 'description': 'In the adaptive arm at Randomisation 1, participants will receive IRD induction therapy with up-front dose reductions adjusted according to their frailty score: fit, unfit, or frail.', 'interventionNames': ['Drug: R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - adaptive arm']}
- {'label': 'R2: Lenalidomide plus placebo maintenance', 'type': 'ACTIVE_COMPARATOR', 'description': 'Participants randomised to this arm at Randomisation 2 will receive lenalidomide plus placebo maintenance.', 'interventionNames': ['Drug: R2: Lenalidomide plus placebo maintenance']}
- {'label': 'R2: Lenalidomide + ixazomib maintenance', 'type': 'EXPERIMENTAL', 'description': 'Participants randomised to this arm at Randomisation 2 will receive lenalidomide plus ixazomib maintenance.', 'interventionNames': ['Drug: R2: Lenalidomide + ixazomib maintenance']}

Interventions:
- {'type': 'DRUG', 'name': 'R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - reactive arm', 'description': 'In the reactive arm at Randomisation 1, participants will receive IRD induction therapy with standard up-front dosing, with toxicity assessed at each cycle and doses adjusted in accordance with the guidelines given in the trial protocol. All participants will be given the following starting doses:\n\nIxazomib: 4mg/day on days 1, 8 and 15, taken orally\n\nLenalidomide: 25mg/day on days 1-21, taken orally\n\nDexamethasone: 40mg on days 1, 8, 15 and 22 for participants aged ≤75 years, or 20mg on days 1, 8, 15 and 22 for participants aged \\> 75 years; taken orally\n\nParticipants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.', 'armGroupLabels': ['R1: IRD induction therapy (reactive)'], 'otherNames': ['Ninlaro', 'Revlimid']}
- {'type': 'DRUG', 'name': 'R1: Ixazomib, Lenalidomide, Dexamethasone (IRD) induction therapy - adaptive arm', 'description': 'In the adaptive arm at Randomisation 1, participants will receive IRD induction therapy with up-front dose reductions adjusted according to their frailty score: fit, unfit, or frail. The starting doses for each frailty category are described below:\n\n1. Fit category:\n\n   Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 25mg on days 1-21, taken orally Dexamethasone: 40mg on days 1, 8, 15 and 22, taken orally\n2. Unfit category:\n\n   Ixazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 15mg on days 1-21, taken orally Dexamethasone: 20mg on days 1, 8, 15 and 22, taken orally\n3. Frail category:\n\nIxazomib: 4mg/day on days 1, 8 and 15, taken orally Lenalidomide: 10mg on days 1-21, taken orally Dexamethasone: 10mg on days 1, 8, 15 and 22, taken orally\n\nParticipants will receive this dosing regimen for 12 cycles of induction treatment, in the absence of disease progression or unacceptable toxicity. Each cycle is 28 days.', 'armGroupLabels': ['R1: IRD induction therapy (adaptive)'], 'otherNames': ['Ninlaro', 'Revlimid']}
- {'type': 'DRUG', 'name': 'R2: Lenalidomide plus placebo maintenance', 'description': 'Participants randomised to receive lenalidomide plus placebo maintenance at Randomisation 2 will receive the following starting doses:\n\nLenalidomide: 10mg\\*/day on days 1-21, taken orally Placebo: 4mg\\*/day on days 1, 8 and 15\n\n\\* or final dose administered at the end of induction treatment if lower.\n\nThis dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days.\n\nRandomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.', 'armGroupLabels': ['R2: Lenalidomide plus placebo maintenance'], 'otherNames': ['Revlimid']}
- {'type': 'DRUG', 'name': 'R2: Lenalidomide + ixazomib maintenance', 'description': 'Participants randomised to receive lenalidomide plus ixazomib maintenance at Randomisation 2 will receive the following starting doses:\n\nLenalidomide: 10mg\\*/day on days 1-21, taken orally Ixazomib: 4mg\\*/day on days 1, 8 and 15\n\n\\* or final dose administered at the end of induction treatment if lower.\n\nThis dosing regimen is continued for every maintenance cycle. Participants will continue maintenance treatment until disease progression or intolerance/unacceptable toxicity. Each maintenance cycle is 28 days.\n\nRandomisation 2 is double-blind - participants and their treating clinicians will be blinded to maintenance allocation.', 'armGroupLabels': ['R2: Lenalidomide + ixazomib maintenance'], 'otherNames': ['Revlimid', 'Ninlaro']}

Primary Outcomes:
- {'measure': 'Randomisation 1: Number of participants with early treatment cessation', 'description': 'Early treatment cessation is defined as a binary endpoint. Participants will be defined to have experienced an event if they die, progress, or are withdrawn from treatment (by a treating clinician) or withdraw consent for trial treatment, within 60 days of Randomisation 1.', 'timeFrame': 'Within 60 days of Randomisation 1'}
- {'measure': 'Randomisation 2: Progression-free survival (PFS-R2)', 'description': 'PFS-R2 is defined as the time from Randomisation 2 to the time of first documented evidence of disease progression or death from any cause. Individuals who are lost to follow-up or progression-free at the time of analysis will be censored at their last known date to be alive and progression-free. Disease progression is defined according to the IMWG Uniform Response Criteria for Multiple Myeloma.', 'timeFrame': 'The time from the date of Randomisation 2 to the date of first documented evidence of disease progression or death from any cause, up to 120 months'}

Please estimate the sample size based on the assumption: 
Calculations are based on a Pearson’s χ2 test without continuity correction, assume a two-sided 5% level of significance, 80% power, and allow for a 1% dropout prior to 60 days post randomisation. For R2, calculations assume a two-sided 5% significance level, 80% power, and allow for a 3% dropout rate prior to a PFS event. 80% power is attained when 302 events have been observed. OS requires 180 events with a minimum of 2-year follow-up for all participants for 80% power.
Sample size
        In total, 740 participants will be enrolled into the trial at R1 to ensure that at least 478 participants remain on trial and are randomised to R2. It is assumed that 65% of those randomised at R1 will be progression free and, therefore, eligible for R2, hence 740 participants are required to be enrolled.
        Based on data from the Myeloma XI non-intensive pathway, we hypothesise the frail and unfit patients in R1 will be similar to the older patients in Myeloma XI (>75 years) who have an early treatment cessation rate (within 60 days of R1) of 20%. This hypothesis is based on the expectation that the frailty score is heavily driven by patient age. Younger patients (â¤75 years) in the Myeloma XI non-intensive pathway have an early treatment cessation rate of 9%, and it is our hypothesis that our frailty-based dosing schedule has the potential to reduce the rate among the unfit and frail patients to the proportion observed in fit patients.28 29
        To demonstrate a decrease of 11% in the proportion of early treatment cessation from 20% in the standard dosing schedule arm to 9% in the frailty score-adjusted dose arm among those patients scored at baseline to be unfit or frail would require the recruitment of 324 patients with an allocation ratio of 1:1. These calculations are based on a Pearsonâs Ï2 test without continuity correction, assume a two-sided 5% level of significance, 80% power, and allow for a 1% dropout prior to 60 days post randomisation. Given that we anticipate that 45% of patients will be scored as unfit or frail, by assuming this trial will have a similar underlying population as in Myeloma XI non-intensive pathway and the age distributions in the IMWG report proposing the frailty score,14 we would anticipate that we will require 720 patients to enter the trial at R1 to have sufficient unfit and frail patients available to answer this question.
        For R2, in the non-intensive pathway of Myeloma XI, the median PFS for patients on R following CRDa induction was approximately 33 months,19 where approximately 65% of individuals were progression-free 12 months post randomisation. As R2 is approximately 12 months following R1 in FiTNEss, we assume that the median PFS for patients receiving R maintenance therapy will be 21 months from R2. Tourmaline-MM112 demonstrated an HR for PFS of 0.74 when comparing IRD and RD in patients with relapsed and refractory multiple myeloma. Thus a similar HR would be the minimum clinically relevant difference for our comparison in patients with newly diagnosed multiple myeloma. Assuming a median PFS of 29 months for those in the R+I maintenance group in addition to the assumption of 21 months in the R group equates to an HR of 0.72.
        The above assumptions require the recruitment of 478 participants over a 30 month recruitment period with a further 24 months of follow-up. These calculations also assume a two-sided 5% significance level, 80% power and allow for a 3% dropout rate prior to a PFS event being experienced. Note that 80% power is attained when 302 events have been observed. A total of 740 participants should be allocated to R1 to ensure that 478 participants are available at the second randomisation.
        OS is considered to be a key secondary endpoint for R2, 180 events with a minimum of 2-year follow-up for all participants are required for 80% power.