Evaluation of Ketamine and Midazolam Hydrochloride in Obsessive-Compulsive Disorder: A Randomized, Double-Blind, Placebo-Controlled Crossover Study

The primary objective of this study is to evaluate the **efficacy** of ketamine in the treatment of **Obsessive Compulsive Disorder (OCD)**. This is clinically relevant as OCD is a chronic and debilitating condition, and current treatment options are limited in their effectiveness for many patients. By assessing ketamine's efficacy, the study aims to explore a potential new therapeutic avenue that could offer relief for individuals with OCD who do not respond adequately to existing treatments.

The clinical trial focuses on evaluating the efficacy of **ketamine** in individuals diagnosed with **Obsessive Compulsive Disorder (OCD)**. The study population includes both male and female participants, aged 18 years and older, who have a primary diagnosis of OCD. Participants must have a score of 16 or higher on the Yale-Brown Obsessive-Compulsive Scale and have undergone at least one previous treatment for OCD. The trial does not involve a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that participants are capable of providing written informed consent, indicating a general level of cognitive and physical health sufficient to engage in the study. The trial population was selected based on these criteria to ensure the reliability and validity of the study outcomes.

The clinical trial is designed to evaluate the **efficacy** of **ketamine** in treating **Obsessive Compulsive Disorder (OCD)**. This is a randomized, double-blind, controlled, cross-over trial comparing ketamine to **midazolam** as a control. The trial is exploratory in nature, classified as Category 2, and aims to assess the therapeutic potential of ketamine in a new indication. The trial is expected to commence recruitment on November 13, 2024, and conclude by September 1, 2026.

Participants will undergo a series of study visits, beginning with an inclusion visit where eligibility is confirmed based on criteria such as a primary diagnosis of OCD, a score of 16 or higher on the Yale-Brown Obsessive-Compulsive Scale, and previous treatment for OCD. The trial will include multiple follow-up visits to monitor the effects of the treatment, with primary endpoints focusing on changes in YBOCS scores before and after ketamine infusion compared to midazolam. Secondary endpoints will assess various neuropsychological and stress response measures.

The expected duration of participant involvement is up to 8 weeks, with conditions for early termination including adverse reactions or withdrawal of consent. The study will involve a sequence of infusions, with ketamine administered at a maximum daily dose of 0.5 mg/kg and midazolam at 0.05 mg/kg. The trial will utilize a per protocol set for secondary endpoints, ensuring rigorous assessment of the treatment's impact on OCD symptoms and related neuropsychological functions.

The clinical trial involves the administration of **Midazolam 5 mg/ml**, a **solution for injection/infusion**. The active substance in this formulation is **midazolam hydrochloride**, a chemical compound. The pharmaceutical form is a solution intended for infusion, and it is manufactured by Hameln Pharma Ltd. The maximum daily dose is 0.05 mg/kg, with a total maximum dose of 0.05 mg/kg over a treatment period of 1 day. The administration route is via infusion, and the product is not a pediatric formulation. Participant compliance will be monitored through standard clinical trial procedures to ensure adherence to the dosing schedule.

In addition to Midazolam, the trial also utilizes **Ketamine 50 mg/ml Injection**, another **solution for injection/infusion**. The active substance is **ketamine**, also a chemical compound, provided by Hameln Pharma Ltd. The maximum daily dose for ketamine is 0.5 mg/kg, with a total maximum dose of 4.5 mg/kg over a treatment period of 8 days. This product is administered via infusion and is not formulated for pediatric use. As with Midazolam, participant compliance will be closely monitored to ensure proper dosing and administration throughout the trial.

The efficacy of ketamine in the treatment of **Obsessive-Compulsive Disorder (OCD)** will be assessed through a series of primary and secondary endpoints. The primary endpoint involves evaluating the difference in changes in Yale-Brown Obsessive-Compulsive Scale (YBOCS) scores before and 7 days after ketamine infusion compared to midazolam infusion. This will be tested in an intention-to-treat set. Secondary endpoints include several measures: the difference in changes in OCD Visual Analogue Scale (OCD-VAS) scores between period-specific baseline and 24 hours after ketamine infusion compared to midazolam infusion, tested in a per protocol set; the difference in changes in YBOCS scores between period-specific baseline and 24 hours after ketamine infusion compared to midazolam infusion, also tested in a per protocol set; and the difference between areas under the curve of OCD-VAS over the course of 7 days, starting with ketamine and midazolam infusion, respectively, tested in a per protocol set.

Additional secondary endpoints include the difference in changes in neuropsychological function under stress between baseline and 24 hours post-infusion, measured by Wisconsin Card Sorting Test (WCST), Stop-Signal Reaction Time (SSRT), N-back, and Tower of Hanoi (ToH), tested in a per protocol set. Hormonal stress response changes will be measured by salivary cortisol levels, summarized as an area under the curve (AUC) for each period, and vegetative stress response changes will be measured by blood pressure, heart rate, and subjective stress VAS scores, also summarized as an AUC for each period. Furthermore, the study will assess the difference in changes in OCD-VAS and YBOCS scores between period-specific baseline and a month after open-label treatment compared to treatment as usual, tested in a per protocol set.