The study will employ a randomized, allocation-concealed, multicenter, placebo-controlled, multi-period crossover design (Schmid et al, 2018). This multi-period crossover randomized, controlled trial allows comparability and assessment of efficacy through repeated exposures within each subject to the active treatment and a control (placebo) in randomized sequence. Such multi-period crossover designs are ideal for treatments with rapid onset of action and short half-life such as the asset under study here. We have strived to minimize the complexity of this powerful design by using only 2 blocks with 2 periods each. The modest additional complexity of the proposed multi-period crossover design, compared to a parallel-groups design, is justified by the marked improvement in efficiency. The gains in efficiency afforded by the multi-period crossover design allow a substantial reduction in sample size without sacrificing statistical power. For example, our simulation experiments (with sample sizes ranging from 30 to 50, carryover effects ranging from 0 to 0.2, and an effect size of 0.4) indicated that the parallel design yields statistical power ranging from 0.20-0.25, whereas our proposed 2-block multi-period crossover design yields power ranging from 0.9-1.0.~The trial will compare an active treatment vs. placebo. Each arm of the study will employ a multi-period crossover design with two blocks. Each block will consist of two treatment periods with each period lasting 6 weeks. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two periods within each block. The period length of 6 weeks was chosen based on several considerations: (i) Most efficacious analgesic drugs demonstrate separation from placebo by 6 weeks; (ii) The decision to move CNTX-6970 forward to Phase 3 will require a clinically meaningful separation from placebo by 6 weeks; (iii) In this Phase 2 study, implementing a treatment block longer than 6 weeks would make the overall design more challenging and burdensome by extending the duration of overall testing beyond 6 months; (iv) Recent meta-analyses suggest that anti-inflammatory treatments such as NSAIDs reach peak effects on pain within a 4-week timeframe in patients with knee osteoarthritis, and multiple RCTs have specifically demonstrated efficacy for celecoxib at 2-6 weeks (Osani et al, 2020).~The comparison with celecoxib is used to evaluate assay sensitivity, i.e., to assess the study protocol's ability to demonstrate superiority of an established efficacious treatment (celecoxib 100mg BID). In this study, the placebo will consist of inactive tablets identical to the active treatment tablets. Treatment assignments (active drug versus placebo) will be randomized for each patient to the two treatment periods within each block
The primary objective of this study is to evaluate the safety and efficacy of two doses of CNTX-6970 for the treatment of pain related to OA of the knee compared to placebo. CNTX-6970 is being developed as a new treatment for chronic pain, including painful osteoarthritis of the knee.