The Kite Trial: Examining the Effectiveness of Ketamine for Adults with Bipolar Depression

Intervention

Intervention code Treatment: Drugs

Randomised Controlled Trial (RCT) Phase: The intervention in the Kite trial during the 3-week RCT treatment phase is low-dose subcutaneous ketamine, administered twice a week. The starting dose for ketamine will be 0.6 mg/kg, or 0.025 mg/kg of midazolam (Level 1). Dose levels may be titrated at subsequent treatment visits in a step-wise manner, with the maximum dose level being Level 4 and the lowest level being Level 0. Between dose levels 1 and 3, there are 0.25 mg/kg increments in ketamine an .... Randomised Controlled Trial (RCT) Phase: The intervention in the Kite trial during the 3-week RCT treatment phase is low-dose subcutaneous ketamine, administered twice a week. The starting dose for ketamine will be 0.6 mg/kg, or 0.025 mg/kg of midazolam (Level 1). Dose levels may be titrated at subsequent treatment visits in a step-wise manner, with the maximum dose level being Level 4 and the lowest level being Level 0. Between dose levels 1 and 3, there are 0.25 mg/kg increments in ketamine and 0.0075 mg/kg in midazolam. The final dose level increment from level 3 to level 4 is 0.2 mg/kg of ketamine and 0.010 mg/kg of midazolam. Treatments will be administered twice per week, with sessions separated by a minimum of two days. The total duration of the RCT phase is 3 weeks, with a maximum of 6 treatments received in this period. The study drug will be administered via subcutaneous injection which will be performed by a research team member, specifically a trained nurse or study doctor, with confirmed proficiency in subcutaneous administration and controlled drug management, adhering to Australian clinical trial and local state regulations and Good Clinical Practice (GCP). The Montgomery-Asberg Depression Rating Scale (MADRS) will be administered immediately before RCT treatments 2, 3, 4, 5, and 6, or within 24 hours prior to the planned administration of these treatments. Participants with inadequate treatment response – defined as less than a 50% reduction in baseline scores on the MADRS) – will receive an increased dose at that treatment session if the previous dose was well-tolerated. Tolerability of the acute response to treatment post-administration will also be assessed using the standardised Ketamine Side-Effects Tool (KSET), the Brief Psychiatric Rating Scale (BPRS), and the Clinician Administered Dissociative Symptoms Scale-6 Item (CADSS-6) questionnaire. Those who are unable to tolerate dose levels 1 - 4 may be down-titrated to lower levels. Participants who are unable to tolerate the starting dose will have their dosage reduced for subsequent treatments to the minimum dose of 0.5 mg/kg. All treatments are administered in person by a member of the study team. Adherence to treatments will be monitored by the study team through regular checks at the study site. Each treatment will be entered into the study-specific database to ensure adherence. Open Label Extension (OLE) Phase: Participants who continue into the OLE phase may receive an additional three weeks of twice-weekly open-label ketamine. Entry into the OLE phase will occur within three-to-four days after completion of the last RCT phase treatment. Dose titration will follow the same methodologies outlined during the RCT phase. However, participants who were randomised to receive ketamine during the RCT phase will start their OLE treatment at the last dose level of the RCT phase and may be titrated according to response and tolerability at subsequent treatment visits.
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Comparison

Control group Active

Randomised Controlled Trial (RCT) Phase: The active placebo control treatment being tested in this study is low- dose midazolam, administered subcutaneously via injection into the abdomen. The active placebo control treatment will only be administered during the RCT phase of the trial. The control treatment during the 3-week Randomised Controlled Trial (RCT) treatment phase is low-dose subcutaneous midazolam, administered twice a week. The starting dose for midazolam will be 0.025 mg/kg (Level 1 .... Randomised Controlled Trial (RCT) Phase: The active placebo control treatment being tested in this study is low- dose midazolam, administered subcutaneously via injection into the abdomen. The active placebo control treatment will only be administered during the RCT phase of the trial. The control treatment during the 3-week Randomised Controlled Trial (RCT) treatment phase is low-dose subcutaneous midazolam, administered twice a week. The starting dose for midazolam will be 0.025 mg/kg (Level 1). Dose levels may be titrated at subsequent treatment visits in a step-wise manner, with the maximum dose level being Level 4 and the lowest level being Level 0. Between dose levels 1 and 3, there are 0.0075 mg/kg increments in midazolam. The final dose level increment from level 3 to level 4 is 0.010 mg/kg of midazolam. Treatments will be administered twice per week, with sessions separated by a minimum of two days. The total duration of the RCT phase is 3 weeks, with a maximum of 6 treatments received in this period. The study control treatment will be administered via subcutaneous injection which will be performed by a research team member, specifically a trained nurse or study doctor, with confirmed proficiency in subcutaneous administration and controlled drug management, adhering to Australian clinical trial and local state regulations and Good Clinical Practice (GCP). The Montgomery-Asberg Depression Rating Scale (MADRS) will be administered immediately before RCT treatments 2, 3, 4, 5, and 6, or within 24 hours prior to the planned administration of these treatments. Participants with inadequate treatment response – defined as less than a 50% reduction in baseline scores on the MADRS) – will receive an increased dose at that treatment session if the previous dose was well-tolerated. Tolerability of the acute response to the control treatment post-administration will also be assessed using the standardised Ketamine Side-Effects Tool (KSET), the Brief Psychiatric Rating Scale (BPRS), and the Clinician Administered Dissociative Symptoms Scale-6 Item (CADSS-6) questionnaire. Those who are unable to tolerate dose levels 1 - 4 may be down-titrated to lower levels. Participants who are unable to tolerate the starting dose will have their dosage reduced for subsequent treatments to the minimum dose of 0.025 mg/kg of midazolam. All control treatments are administered in person by a member of the study team. Adherence to treatments will be monitored by the study team through regular checks at the study site. Each treatment will be entered into the study-specific database to ensure adherence. Open Label Extension (OLE) Phase: Participants who were randomised to the active placebo control condition in the RCT Phase and who continue into the OLE phase may receive three weeks of twice-weekly open-label ketamine treatment. Entry into the OLE phase will occur within three-to-four days after completion of the last RCT phase treatment. Dose titration will follow the same methodologies outlined during the RCT phase. Participants who were randomised to the active placebo control condition during the RCT phase will begin at ketamine dose level 1 (0.6 mg/kg) at the first treatment in the OLE phase. The dosage may be titrated according to response and tolerability at subsequent OLE treatments, as per the methodology outlined in the RCT phase.
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Outcomes

Outcome: Effect of low-dose subcutaneous ketamine in comparison to midazolam control on depression symptoms in adults with bipolar depression.
Timepoint: Baseline, Day4, Day 8, Day 11, Day 15, Day 18, Day 19 (primary timepoint; 19 days post commencement of treatment).