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Multi-center RCT of IV Ketamine Efficacy and Safety in Chronic Daily Headaches (KetHead)

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ClinicalTrials.gov Identifier: NCT05306899
Recruitment Status : Not yet recruiting
First Posted : April 1, 2022
Last Update Posted : June 1, 2022
Sponsor:
Collaborators:
The Canadian Pain Society
Pfizer
Information provided by (Responsible Party):
University Health Network, Toronto

Tracking Information
First Submitted Date  ICMJE March 2, 2022
First Posted Date  ICMJE April 1, 2022
Last Update Posted Date June 1, 2022
Estimated Study Start Date  ICMJE June 1, 2022
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 22, 2022)
Difference in headache days between the 2 groups [ Time Frame: At 4 weeks ]
Between-group difference in the number of headache days in the first 4 weeks after the infusion. (Defined as a day in which the headache lasts 4 or more hours, or a headache of any duration for which abortive treatment (anti-inflammatories, triptans, ergot derivatives, opioids) are taken. Patients will be asked to keep track of their headache days in a diary)
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: March 22, 2022)
  • Impact of ketamine on headache intensity after infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on headache intensity at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using Numerical Rating Scale (0-10)
  • Impact of ketamine on headache frequency after infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on headache frequency at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, as number of headache episodes per day
  • Impact of ketamine on headache duration after infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on duration of headache at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, from the headache diary maintained by patient
  • Impact on sleep efficiency after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on efficiency of sleep at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with an actigraphy device
  • Impact on quality of sleep after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on quality of sleepat one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, assessed with the PSQI (Pittsburgh Sleep Quality Index) questionnaire
  • Impact on physical activity after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on physical activity at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with actigraphy device
  • Impact after ketamine infusion on daily activity [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on seven daily activities (e.g. general activity, walking, mood etc.) at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, measured with Brief Pain Inventory (BPI) scale
  • Impact of on emotional well being (for catastrophizing) after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using the PCS (pain catastrophizing scale) scale
  • Impact of on emotional well being for anxiety after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using anxiety (GAD7- Generalized Anxiety Disorder-7) scale
  • Impact of on emotional well being for depression after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on emotional well being at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using depression (PHQ9-Patient Health Questionnaire9) questionnaire
  • Impact of ketamine infusion on patient satisfaction [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on patient satisfaction at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using global improvement (PGIC) scales
  • Impact on quality of life after ketamine infusion [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on quality of life at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using EQ-5D (European Quality of life) questionnaire
  • Impact of ketamine infusion on analgesic consumption [ Time Frame: At 1 month, 2 months and 3 months ]
    Impact of ketamine on analgesic consumption at one month (4 weeks), two month (week 5-8) and three month (week 9-12) month after infusion, using name and dose of the analgesic use
  • Side effects after ketamine infusion [ Time Frame: Immediately after infusion and after 1 week ]
    Side effects after the ketamine infusion as assessed using Bowdle questionnaire
  • Side effects after ketamine infusion [ Time Frame: Immediately after the infusion ]
    Dissociative side effects assessed after the ketamine infusion, using the CADSS (Clinician Administered Dissociative States Scale) checklist
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Multi-center RCT of IV Ketamine Efficacy and Safety in Chronic Daily Headaches
Official Title  ICMJE A Multi-center Randomized Controlled Trial of Efficacy and Safety of Intravenous Ketamine for Chronic Daily Headaches: The KetHead Study
Brief Summary

Chronic daily headaches (CDH) poses a significant burden on patients, healthcare systems and the society. Intravenous (IV) ketamine infusion, an intervention that is widely available and scalable, can treat CDH by reversing receptor-mediated sensitization. This study is a multicenter, placebo-controlled, parallel group randomized trial with blinding of participants and observers with the goal of comprehensively assessing the effect of high-dose IV ketamine infusion (1 mg.kg-1.h-1 for six hours) on the frequency and intensity of headaches, mood, activity, sleep, quality of life and safety of ketamine for three months after the interventions. Use of validated questionnaires, wearable technology, a research team that includes investigators with expertise in studying ketamine and in evaluating treatments for CDH and pain syndromes are some of the unique features of this project.

Our study aims to prospectively assess the efficacy and safety of high-dose intravenous ketamine infusions compared to saline infusions in participants with CDH syndrome.

Detailed Description

The KetHead study is designed as a multi-center, placebo-controlled, superiority randomized controlled trial with two parallel groups and blinding of participants and outcome assessors. It will be conducted at two chronic pain centers, Toronto Western Hospital and Sinai Health System. Eligible patients will be identified and enrolled in the pain clinics. Randomization will take place upon patient enrollment. Treating physicians, patients, close contacts, study coordinators and primary outcome assessors will be blinded to treatment allocation.

Interventions common to both arms Participating patients will receive the infusion at the pain infusion unit at Toronto Western Hospital, under hemodynamic monitoring, supervised by an Anesthesiologist. At the start of the infusion, all patients will receive IV midazolam 0.04 mg.kg-1 (maximum 3 mg) and subsequently 0.01-0.02 mg.kg-1 every hour to keep participants in a sedated but arousable state (Ramsay Sedation Scale score 3 or 4)22 to blind the participants and assessors to group allocation. Eight mg of ondansetron and 8 mg of dexamethasone will be administered to all participants to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events. Medications will be administered by an Anesthesiologist.

A. Intervention group: For individuals randomized to the IV Ketamine group, 1 mg.kg-1 bolus will be given. This will be prepared as a syringe of 10 cc of Ketamine 10 mg/ml. This is followed by an infusion of 1 mg.kg-1.hour-1 (ketamine diluted in saline to 2 mg/mL at 0.5 mL.kg-1.hour-1) for six hours.

B. Control group: For individuals in the saline infusion group, an IV bolus of 0.9% saline will be given. The volume will be the same as that of the ketamine bolus for that weight, to prevent unblinding of participants and assessors. This will be followed by an infusion 0.5 mL.kg-1.hour-1 of saline for six hours. The rate of the infusion will be the same as that of a ketamine infusion for that weight to prevent unblinding of participants and assessors.

Study personnel will assess patient and collect data throughout their enrollment in the study.

During the trial, patients will be instructed to use a pain and migraine diary for collection of migraine days, pain scores and rescue pain medication during the 12 weeks after infusion.

Patients will be assessed for collection of outcomes immediately after the infusion and at 1-month, 2-months and 3-months after infusion.

Participants in both arms will wear the actigraphy device starting on the day of infusion for one month to longitudinally assess the impact of the study treatments on sleep and activity.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Care Provider)
Primary Purpose: Treatment
Condition  ICMJE Chronic Daily Headache
Intervention  ICMJE
  • Drug: Ketamine
    Bolus of IV Ketamine 1 mg.kg-1 (= 0.1 ml.kg-1) followed by Infusion of Ketamine 1 mg.kg-1.hour-1 (= 0.5 mL.kg-1.hour-1) for 6 hours. All patients will receive IV midazolam 0.04 mg.kg-1 (maximum 3 mg) and subsequently 0.01-0.02 mg.kg-1 every hour to keep participants in a sedated but arousable state (Ramsay Sedation Scale score 3 or 4) to blind the participants and assessors to group allocation. Ondansetron 8 mg and 8 mg of dexamethasone will be administered to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events.
    Other Name: Ketamine hydrochloride
  • Other: 0.9% Saline
    Bolus of IV Saline 0.9% of 0.1 ml.kg-1 followed by Infusion of Saline 0.9% of 0.5 mL.kg-1.hour-1 for 6 hours. All patients will receive IV midazolam 0.04 mg.kg-1 (maximum 3 mg) and subsequently 0.01-0.02 mg.kg-1 every hour to keep participants in a sedated but arousable state (Ramsay Sedation Scale score 3 or 4) to blind the participants and assessors to group allocation. Ondansetron 8 mg and 8 mg of dexamethasone will be administered to prevent nausea, 5000 units of heparin will be given subcutaneously to prevent thrombo-embolic events.
    Other Name: Normal saline
Study Arms  ICMJE
  • Active Comparator: Ketamine infusion
    Intravenous Ketamine
    Intervention: Drug: Ketamine
  • Placebo Comparator: Placebo infusion
    Intervention: Other: 0.9% Saline
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Not yet recruiting
Estimated Enrollment  ICMJE
 (submitted: March 22, 2022)
56
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE February 1, 2024
Estimated Primary Completion Date October 1, 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age 18 years or older
  2. CDH diagnosis preceding trial enrollment with headache episodes lasting for 4 or more hours occurring on 15 or more days in a month for 3 or more months (International Headache Society-IHS criteria)
  3. Normal liver and kidney function tests

Exclusion criteria:

  1. Pregnant or breastfeeding patients
  2. Pre-existing renal impairment
  3. Pre-existing liver impairment
  4. Chronic benzodiazepine or antipsychotic medication use
  5. History of cerebrovascular event
  6. Significant and untreated hypertension or severe cardiac condition
  7. Hypothyroidism
  8. Glaucoma
  9. Concomitant use of strong CYP2B6 or CYP2C8 inhibitor
  10. Allergy or intolerance to ketamine
  11. Pheochromocytoma
  12. Any significant cognitive or language barriers that impede participation
  13. CGRP antagonist use in 1 month or Onabotulinum-toxin A 3 months before infusion
  14. Active diagnosis of Post-Traumatic Stress Disorder (PTSD)
  15. Active diagnosis of Substance Use Disorder
  16. Patients taking opioid medications with daily Oral Morphine Equivalents ≥80 mg
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Kawal P Singh +1 (416) 603 5800 ext 3959 kawalpreet.singh@uhnresearch.ca
Contact: Jamal Kara, BSc Msc +1 (416) 603 5800 ext 6237 Jamal.Kara@uhn.ca
Listed Location Countries  ICMJE Canada
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT05306899
Other Study ID Numbers  ICMJE 21-5523
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Plan Description: Study results will first be disseminated at the local, national and international conferences and submitted for publication in a peer-reviewed journal.
Current Responsible Party University Health Network, Toronto
Original Responsible Party Same as current
Current Study Sponsor  ICMJE University Health Network, Toronto
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE
  • The Canadian Pain Society
  • Pfizer
Investigators  ICMJE
Principal Investigator: Yasmine Hoydonckx, MD, FIPP University Health Network, Toronto
PRS Account University Health Network, Toronto
Verification Date October 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP