<p>Prediction-powered inference (PPI) (Angelopoulos et al., Science 382(6671):669–674, 2023) and its subsequent development called PPI++ (Angelopoulos et al., 2023) provide a novel approach to standard statistical estimation, leveraging machine learning systems, to enhance unlabeled data with predictions. We use this paradigm in clinical trials. The predictions are provided by disease progression models, providing prognostic scores for all the participants as a function of baseline covariates. The proposed method would empower clinical trials by providing untreated digital twins of the treated patients while remaining statistically valid. The potential implications of this new estimator of the treatment effect in a two-arm randomized clinical trial (RCT) are manifold. First, it leads to an overall reduction of the sample size required to reach the same power as a standard RCT. Secondly, it advocates for an imbalance of controls and treated patients, requiring fewer controls to achieve the same power. Finally, this technique directly transfers any disease prediction model trained on large cohorts to practical and scientifically valid use. In this paper, we demonstrate the theoretical properties of this estimator and illustrate them through simulations. We show that it is asymptotically unbiased for the Average Treatment Effect and derive an explicit formula for its variance. We then compare this estimator to a regression-based linear covariate adjustment method. An application to an Alzheimer’s disease clinical trial showcases the potential to reduce the sample size.</p>