BACKGROUND: Successful completion of investigator-initiated pediatric venous thromboembolism (VTE) trials has been hampered when key assumptions in trial design have often not been met during trial execution. Unfortunately, pilot/feasibility (P/F) studies have rarely been conducted and reported prior to implementation of the definitive trials.
METHODS: The Kids-DOTT trial is a multicenter, parallel-cohort randomized controlled trial (RCT) evaluating efficacy and safety of shortened (6 weeks) versus conventional (3 months) duration of anticoagulation in pediatric provoked VTE. The Kids-DOTT design included a pre-specified P/F phase consisting of the first 100 subjects enrolled. Quality assurance methods included real-time remote monitoring of patient eligibility criteria immediately prior to enrollment, as well as measurement of inter-observer agreement of mutually-blinded, central versus local radiologic assessments of complete thrombus veno-occlusion (yes/no) at 6 weeks post-diagnosis (a key randomization criterion in the trial). P/F metrics included: screened:enrolled ratio; radiologic inter-observer agreement (measured by percent agreement and kappa statistic); frequency of protocol violations pertaining to eligibility criteria and randomization procedures; proportion of the enrolled population comprising the non-randomized parallel cohorts; and rates of withdrawal/loss to follow-up. The blind was maintained for all P/F analyses.
RESULTS: Screened:enrolled ratio was approximately 6:1, of which 4% was due to declined consent. During the last 6 months of the P/F phase, with an average of 15 open centers, 24 subjects were enrolled. Protocol violations due to missed randomization occurred in 3% of subjects (3/92) who have reached the 6-week (randomization) visit. There were no eligibility violations and no improper randomizations. During the two most recent years of the trial, 14% of subjects were allocated to the observational, parallel cohorts on completely veno-occlusive thrombosis or persistent antiphospholipid antibody positivity; remaining subjects comprised the RCT population. Inter-observer agreement in the determination of complete veno-occlusion at 6-week imaging (n=71 adjudicated to date) was 97% (95% confidence interval, 89-100%) with Κ=0.79 (95% CI, 0.50-1.0), indicating “substantial agreement” (Landis-Koch criteria). Complete veno-occlusion, as defined by absence of flow throughout a venous segment (e.g. femoral vein; subclavian vein), was observed at 6 weeks in 6% of adjudicated patients (4/71). Rate of withdrawal/loss-to-follow-up prior to primary endpoint assessment was 10% (10/97).
CONCLUSIONS: The P/F phase of the Kids-DOTT trial has provided novel multicenter feasibility data demonstrating substantial inter-observer agreement in radiologic determination of complete thrombus veno-occlusion, and a rate of completely veno-occlusive thrombosis of 6% at 6 weeks following diagnosis of provoked venous thrombosis. In addition, it has defined recruitment and retention rates on the trial that have facilitated determination of the required number of participating sites (40) to complete timely accrual. Kids-DOTT is now continuing toward completion of the definitive RCT, targeted for 2018.
Goldenberg:Eisai Inc: Research Funding. Off Label Use: Anticoagulants for pediatric venous thrombosis, all of which are off-label for this (pediatric) indication despite their use in the pediatric standard of care. .
Asterisk with author names denotes non-ASH members.