Psychiatry · Medical Literature
Oral Prolonged-Release Ketamine for Treatment-Resistant Depression: Two Randomized Clinical Trials.
Abstract
Ketamine exerts rapid antidepressant effects. However, currently available ketamine-based treatments are associated with dissociative and cardiovascular adverse effects. To evaluate the antidepressant efficacy and tolerability of KET01, a novel, oral, prolonged-release racemic ketamine tablet formulation. KET01-03 was an active-comparator, double-blind, double-dummy, crossover phase 1 randomized clinical trial (RCT) conducted among healthy adult male volunteers (aged ≥18 years) between July and August 2023 at a single trial site in Germany. KET01-02 was a placebo-controlled, double-blind phase 2 RCT conducted between May 2022 and May 2023 among adult outpatients (aged ≥18 years) with treatment-resistant depression across 29 trial sites in the Czech Republic, Germany, and Poland. KET01-02 data were analyzed from May to October 2023 and KET01-03 data from August to October 2024. KET01-03 investigated a single dose of KET01 (240 mg) vs intranasal esketamine (84 mg), and KET01-02 evaluated KET01 dosages of 120 or 240 mg/d (adjunctive to ongoing standard therapy) against placebo for 3 weeks. The primary end points were the difference in mean maximum change in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and intranasal esketamine within the first 24 hours in KET01-03 and the least squares (LS) mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) score from baseline to day 21 for 240 mg/d of KET01 vs placebo in KET01-02. KET01-03 randomized 26 males (median age, 32 years [range, 21-45 years]), and KET01-02 randomized 122 outpatients with treatment-resistant depression (72 [59.0%] female; median age, 41 years [range, 19-65 years]). In KET01-03, intranasal esketamine but not KET01 induced significant dissociation within 24 hours after dosing (mean [SD] maximum change in CADSS score, 29.6 [12.5] points vs 0.7 [1.7] points; P < .001). The maximum plasma concentration was lower for KET01 (39.1 ng/mL) than esketamine (104.1 ng/mL); conversely, exposure to metabolites was higher for KET01 (eg, area under the curve [AUC] from baseline to last measurement for norketamine was 3.5 µg × h/mL) than esketamine (AUC for [S]-norketamine, 1.4 µg × h/mL). Pulse and blood pressure did not change markedly in the KET01 group in both trials, in contrast to rapid increases after intranasal esketamine in KET01-03. In KET01-02, the primary efficacy end point at day 21 was not met: LS mean MADRS score difference for 240 mg/d of KET01 vs placebo was -1.82 points (95% CI, -6.21 to 2.57 points; P = .41). However, a reduction in MADRS scores was observed 7 hours after administering the first 240 mg dose of KET01, with an LS mean difference vs placebo at day 4 (-3.66 [95% CI, -6.74 to -0.59] points; nominal P = .02) and day 7 (-3.95 [95% CI, -7.75 to -0.15] points; nominal P = .04). During follow-up, the LS mean MADRS point difference vs placebo at 4 weeks was -3.35 (95% CI, -7.62 to 0.93; nominal P = .13). The antidepressant properties and tolerability profile of KET01 in these RCTs, including minimal dissociation and cardiovascular effects, support further development of oral KET01 formulation for at-home administration. EU Clinical Trials Register Identifiers: 2023-503971-45-00 and 2021-004927-34.
Clinical relevance
In adults with treatment-resistant depression (TRD), does oral prolonged-release racemic ketamine (KET01) produce antidepressant efficacy superior to placebo over 3 weeks when added to standard therapy, and does it cause significantly less dissociation and cardiovascular effects than intranasal esketamine? __SNAPSHOT__ {"studyDesign":"Two linked randomized clinical trials reported together: (1) KET01-03 — Phase 1, active-comparator, double-blind, double-dummy, crossover RCT in healthy volunteers; (2) KET01-02 — Phase 2, placebo-controlled, double-blind, parallel-group RCT in outpatients with TRD","setting":"KET01-03: single site, Germany (July–August 2023). KET01-02: 29 outpatient sites across Germany, Czech Republic, and Poland (May 2022–May 2023)","sampleSize":"KET01-03: n=26 healthy adult males. KET01-02: n=122 adult outpatients with TRD (placebo: ~40; KET01 120 mg/d: ~42; KET01 240 mg/d: ~40)","population":"KET01-03: Healthy adult males ≥18 years (median age 32 years, range 21–45). KET01-02: Adult outpatients ≥18 years with treatment-resistant depression (72 [59.0%] female; median age 41 years, range 19–65), receiving ongoing standard antidepressant therapy","intervention":"KET01-03: Single oral dose of KET01 240 mg. KET01-02: Once-daily oral KET01 120 mg/d or 240 mg/d adjunctive to ongoing standard antidepressant therapy for 3 weeks","comparator":"KET01-03: Single dose intranasal esketamine 84 mg (double-dummy crossover). KET01-02: Matched oral placebo adjunctive to ongoing standard antidepressant therapy","primaryOutcome":"KET01-03: Difference in mean maximum change in Clinician-Administered Dissociative States Scale (CADSS) score between KET01 and intranasal esketamine within the first 24 hours. KET01-02: Least squares (LS) mean change in MADRS total score from baseline to Day 21 for KET01 240 mg/d vs. placebo","followUp":"KET01-03: 24-hour primary assessment window; KET01-02: 21-day treatment phase plus approximately 4-week post-treatment follow-up period","fundingSource":"Industry — trials conducted and funded by Ketabon GmbH, a joint venture of HMNC Brain Health (HMNC Holding GmbH) and Develco Pharma Schweiz AG. The sponsor had an active role in design, conduct, data analysis, manuscript preparation, and publication decision."}
Key findings
KET01-03 (tolerability/pharmacokinetic trial): Intranasal esketamine produced substantial dissociation while KET01 did not. The mean (SD) maximum CADSS score change was 29.6 (12.5) points for esketamine vs. 0.7 (1.7) points for KET01 (P<.001). Incidence of any dissociation was 96% in the esketamine group vs. 4% in the KET01 group. Treatment-emergent adverse events (TEAEs) within the first 48 hours were reported in 100% of the esketamine group and 62% of the KET01 group. Blood pressure and pulse increased rapidly with esketamine but remained stable with KET01 in both trials. Pharmacokinetically, maximum plasma concentration was lower for KET01 (39.1 ng/mL) than esketamine (104.1 ng/mL), while metabolite exposure was substantially higher with KET01 (norketamine AUC 3.5 µg×h/mL vs. [S]-norketamine AUC 1.4 µg×h/mL for esketamine). No serious adverse events were reported in KET01-03. KET01-02 (efficacy trial): The primary endpoint was not met. The LS mean MADRS score difference for KET01 240 mg/d vs. placebo at Day 21 was −1.82 points (95% CI, −6.21 to 2.57; P=.41). However, statistically significant MADRS reductions vs. placebo were observed at Day 4 (LS mean difference −3.66 points; 95% CI, −6.74 to −0.59; nominal P=.02) and Day 7 (−3.95 points; 95% CI, −7.75 to −0.15; nominal P=.04). Patients receiving KET01 240 mg/d showed an overall within-group change from baseline of −13.15 MADRS points across the treatment period. A clinical response rate of 47.5% and remission rate of 40.0% were observed in the KET01 240 mg/d group at Day 21. The placebo clinical response rate was 37.5% — a substantial placebo response that attenuated between-group differences. TEAEs were reported in 47.5% (placebo), 50.0% (120 mg/d KET01), and 62.5% (240 mg/d KET01); dizziness (17.5%) was the most common TEAE in the 240 mg/d arm. TEAEs potentially related to dissociation occurred in 0% (placebo), 0% (120 mg/d), and 12.5% (240 mg/d) of patients. No treatment-related serious adverse events were reported. NNT for response (KET01 240 mg/d vs. placebo at Day 21: 47.5% vs. 37.5%) = approximately 10 (calculated). The clinical meaningfulness of the observed early MADRS differences of approximately 3.7–4.0 points over placebo is uncertain given that the minimum clinically important difference on the MADRS is generally considered to be approximately 1.6–2.0 points in some references, though 3–4 points is the range often required for regulatory purposes.
Practice implications
What this study established: KET01, an oral prolonged-release racemic ketamine formulation, reliably avoids the dissociative and cardiovascular adverse effects associated with intranasal esketamine at doses being developed for TRD. The pharmacokinetic profile — lower peak ketamine concentration paired with greater norketamine metabolite exposure — provides a plausible mechanistic basis for this improved tolerability. Early antidepressant signals were detected at Days 4 and 7 in the Phase 2 trial. What this study did NOT establish: Antidepressant superiority over placebo at the pre-specified primary endpoint (Day 21 MADRS), which is the regulatory and clinical threshold of interest. The Phase 2 trial was substantially underpowered by conventional standards and was undermined by a high placebo response rate (37.5% clinical response in placebo arm). Whether the early MADRS improvements at Days 4 and 7 are durable, clinically meaningful over weeks-to-months, or reproducible in a larger sample is unknown. Long-term safety (hepatotoxicity, urinary, abuse potential, cognitive effects) with chronic oral administration was not evaluated. Which patients the findings apply to: Adult outpatients aged 19–65 with TRD receiving stable background antidepressant therapy in a European clinical setting; predominantly female (59%). Which patients were not represented: Patients with severe suicidality (likely excluded), older adults, those with comorbid substance use disorder, those not on concurrent antidepressants, and non-European populations. Practice implications: KET01 is not approved and should not be used outside of clinical trials. These results do not support any change in current TRD management practices. The findings justify, but do not substitute for, adequately powered Phase 3 trials with longer follow-up. __LIMITATIONS__ Phase 2 trial (KET01-02) did not meet its pre-specified primary efficacy endpoint; all secondary efficacy analyses should be considered exploratory and hypothesis-generating only.,Small sample sizes in both trials (KET01-03: n=26; KET01-02: n=122) limit power to detect modest but clinically meaningful efficacy differences and to characterize rare adverse events.,KET01-03 enrolled only healthy adult males, severely limiting generalizability of pharmacokinetic and tolerability data to TRD patients, including women.,High placebo response rate (37.5% clinical response) in KET01-02 substantially attenuated between-group separation at Day 21 and may reflect regression to the mean, therapeutic attention effects, or inadequate TRD case ascertainment.,Short treatment duration (21 days) and follow-up insufficient to assess durability of antidepressant response, maintenance of remission, relapse rates, or long-term safety outcomes.,Industry sponsorship with active funder involvement in all aspects of trial design, conduct, data analysis, manuscript preparation, and publication decision introduces a high risk of reporting and framing bias.,Functional unblinding risk: although KET01 produced minimal dissociation, the 12.5% TEAE dissociation rate in the 240 mg/d group and differential side-effect profiles may have partially unblinded some participants.,KET01-03 crossover design with 2–4-week washout: potential carryover effects cannot be fully excluded.,Only 3 weeks of treatment evaluated; chronic dosing effects on hepatic enzymes (GGT transient elevations noted in prior data), urinary tract, and abuse potential are not characterized.,Absence of formal multiplicity correction for the Day 4 and Day 7 MADRS differences means nominal p-values should be interpreted with caution.,Generalizability is limited to European outpatient TRD populations; results may not apply across different healthcare systems, demographic groups, or varying background antidepressant regimens. __BOTTOM_LINE_CATEGORY__ promising_but_preliminary __BOTTOM_LINE__ Oral prolonged-release ketamine (KET01) demonstrated a markedly superior tolerability profile compared to intranasal esketamine — with near-absence of dissociation and cardiovascular effects — providing a biologically and clinically plausible basis for at-home administration. However, the Phase 2 efficacy trial failed to meet its primary endpoint of MADRS reduction at Day 21 versus placebo, largely due to a high placebo response rate, and the study was substantially underpowered. KET01 should not be used outside clinical trials; adequately powered, Phase 3 trials with longer follow-up are required before any practice-informing conclusions about antidepressant efficacy can be drawn.