High Dose Intravenous Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell Transplantation

Delirium is a common and potentially preventable neuropsychiatric complication in cancer patients receiving hematopoietic stem cell transplantation (HSCT) that has profound consequences. Among cancer patients hospitalized for HSCT, delirium occurs in approximately 40% of patients and increases the risk of mortality. Long-term, delirium in this population results in worse physical health, mental health, and quality of life. Though strategies to prevent delirium have the potential to significantly improve the lives of people living with cancer, research in this area is extremely limited. Thiamine deficiency is also ubiquitous during HSCT and a known contributor to the development of delirium in other patient populations. High dose intravenous (IV) thiamine is an evidence-based and promising treatment for delirium, but no one has studied IV thiamine as a prevention strategy.

This is a randomized double-blind controlled trial in participants undergoing allogeneic HSCT to determine if high dose IV thiamine can prevent delirium and minimize the deleterious impact of delirium on health-related quality of life (HRQOL), functional status, and other neuropsychiatric outcomes. The investigators will recruit 60 patients admitted for allogeneic HSCT at UNC, randomize them to treatment with high dose IV thiamine (n = 30) versus placebo (n = 30), and systematically evaluate all participants for delirium and related comorbidities. The investigators will use the Delirium Rating Scale (DRS) to measure the severity and duration of delirium immediately prior to transplant and after HSCT until 30 days post-transplant or discharge. If delirium is identified, the DRS will be administered daily until delirium resolves. The investigators will obtain thiamine levels and other laboratory parameters associated with delirium the day after transplant, and continue to monitor thiamine levels weekly thereafter. The investigators will also monitor HRQOL, functional status, depression, post-traumatic stress symptoms, and cognitive function prior to transplant and at one, three, and six months after transplant to elucidate the persistent impact of delirium in this population and the potential for thiamine to mitigate these negative outcomes.

• Thiamine (Drug), also known as Thiamine Hydrochloride Injection: 200 mg IV three times daily for seven days
• Normal saline (Drug), also known as Placebo: Normal saline IV three times daily for seven days

Primary outcomes

• Percentage of Participants With Delirium [Assessments will occur in the week prior to transplant, then 3 times weekly post-transplant until 30 days post-transplant or discharge, whichever comes first.]: Delirium incidence will be measured using the Delirium Rating Scale (DRS). The DRS is a is a 10-item, clinician-rated scale that rates the severity of delirium symptoms over a 24-hour period using all available information from the patient interview, mental status examination, medical history and tests, nursing observations, and family reports. The maximum possible score is 32. Higher scores suggest more severe symptoms. A cut-off score of > 12 has been suggested to distinguish patients with delirium from patients with other neuropsychiatric disorders. Delirium incidence will be defined as at least one assessment with DRS > 12.

Secondary outcomes

• Delirium Severity [Assessments will occur in the week prior to transplant (baseline), then at least 3 times post-transplant on a weekly basis until 30 days post-transplant or discharge, whichever comes first, up to week 5]: Delirium severity will be measured using the Delirium Rating Scale (DRS). The DRS is a is a 10-item, clinician-rated scale that rates the severity of delirium symptoms over a 24-hour period using all available information from the patient interview, mental status examination, medical history and tests, nursing observations, and family reports. The score ranges from 0 to 32 with higher scores reflecting more severe symptoms. A cut-off score of > 12 has been suggested to distinguish patients with delirium from patients with other neuropsychiatric disorders. The DRS medians and ranges are reported for each group at baseline and in each week of hospitalization for thiamine and placebo groups.
• Delirium Duration [Assessments will occur in the week prior to transplant, then 3 times weekly post-transplant until 30 days post-transplant or discharge, whichever comes first.]: Delirium duration will be measured using the Delirium Rating Scale (DRS). The DRS is a is a 10-item, clinician-rated scale that rates the severity of delirium symptoms over a 24-hour period using all available information from the patient interview, mental status examination, medical history and tests, nursing observations, and family reports. The maximum possible score is 32. Higher scores suggest more severe symptoms. A cut-off score of > 12 has been suggested to distinguish patients with delirium from patients with other neuropsychiatric disorders. Delirium duration will be reported as number of consecutive days during which DRS > 12.
• Concentration of Thiamine Status Stratified by Delirium Status [From end of 7-day intervention period until the development of delirium at any point during the post-transplant hospitalization up to a maximum of 30 days]: The relationship between thiamine levels at the end of the seven day administration of thiamine and the development of delirium at any point during the thirty days post-transplant or the post-transplant hospitalization, whichever comes first, will be examined. Thiamine levels (nmol/L) are presented in participants who did and did not experience delirium.
• Change in Health-related Quality of Life Scores (Month 1) [From baseline to one month post-transplant]: HRQOL will be assessed using the Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT). The FACT-BMT is a 47-item self-administered assessment which asks individuals to rate questions related to physical, social/family, emotional, and functional well-being on a 5-point Likert Scale (0, not at all to 4, very much). Scores are summed across the items, resulting in a score from 0 to 148, with higher scores indicating better quality of life. Negative change scores indicate worse HRQOL with time.
• Change in Health-related Quality of Life Scores (Month 3) [Baseline to three months post-transplant]: HRQOL will be assessed using the Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT). The FACT-BMT is a 47-item self-administered assessment which asks individuals to rate questions related to physical, social/family, emotional, and functional well-being on a 5-point Likert Scale (0, not at all to 4, very much). Scores are summed across the items, resulting in a score from 0 to 148, with higher scores indicating better quality of life. Negative change scores indicate worse HRQOL with time.
• Change in Health-related Quality of Life Scores (Month 6) [Baseline to six months post-transplant]: HRQOL will be assessed using the Functional Assessment of Cancer Therapy - Bone Marrow Transplant (FACT-BMT). The FACT-BMT is a 47-item self-administered assessment which asks individuals to rate questions related to physical, social/family, emotional, and functional well-being on a 5-point Likert Scale (0, not at all to 4, very much). Scores are summed across the items, resulting in a score from 0 to 148, with higher scores indicating better quality of life. Negative change scores indicate worse HRQOL with time.
• Change in Depression Scores (Month 1) [Baseline to one month post-transplant]: Depression will be assessed using the Patient Reported Outcomes Measurement Information System - Depression (PROMIS-D) 8a short form. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of mood symptoms. Positive change scores indicate worse mood over time.
• Change in Depression Scores (Month 3) [Baseline to three months post-transplant]: Depression will be assessed using the Patient Reported Outcomes Measurement Information System - Depression (PROMIS-D) 8a short form. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of mood symptoms. Positive change scores indicate worse mood over time.
• Change in Depression Scores (Month 6) [Baseline to six months post-transplant]: Depression will be assessed using the Patient Reported Outcomes Measurement Information System - Depression (PROMIS-D) 8a short form. Scores for all PROMIS measures are reported on the T-score metric in which the mean=50 and standard deviation (SD) = 10 are centered on the general population means. Higher scores represent greater degrees of mood symptoms. Positive change scores indicate worse mood over time.
• Change in Post-traumatic Stress Symptom Scores (Month 1) [Baseline to one month post-transplant]: Post-traumatic stress symptoms will be measured using the Post Traumatic Stress Syndrome Scale 14 (PTSS-14). The PTSS-14 is a 14-item self-administered assessment. Questions are on a 7-point Likert-type Scale (1, never to 7, always) resulting in a total score between 14 and 98. Higher scores represent a more likely diagnosis of post-traumatic stress disorder (PTSD). Positive change scores indicate worse post-traumatic stress over time.
• Change in Post-traumatic Stress Symptom Scores (Month 3) [Baseline to three months post-transplant]: Post-traumatic stress symptoms will be measured using the Post Traumatic Stress Syndrome Scale 14 (PTSS-14). The PTSS-14 is a 14-item self-administered assessment. Questions are on a 7-point Likert-type Scale (1, never to 7, always) resulting in a total score between 14 and 98. Higher scores represent a more likely diagnosis of post-traumatic stress disorder (PTSD). Positive change scores indicate worse post-traumatic stress over time.
• Change in Post-traumatic Stress Symptom Scores (Month 6) [Baseline to six months post-transplant]: Post-traumatic stress symptoms will be measured using the Post Traumatic Stress Syndrome Scale 14 (PTSS-14). The PTSS-14 is a 14-item self-administered assessment. Questions are on a 7-point Likert-type Scale (1, never to 7, always) resulting in a total score between 14 and 98. Higher scores represent a more likely diagnosis of post-traumatic stress disorder (PTSD). Positive change scores indicate worse post-traumatic stress over time.
• Change in Cognitive Function Scores (Month 1) [From baseline to one month post-transplant]: Cognitive function will be assessed using the Montreal Cognitive Assessment (MOCA). The MOCA is a clinician-administered tool with scores ranging from 0 to 30. Lower scores indicate worse cognitive function. Scores ≤ 25 are considered clinically significant. Positive change scores indicate better function with time.
• Change in Cognitive Function Scores (Month 3) [Baseline to three months post-transplant]: Cognitive function will be assessed using the Montreal Cognitive Assessment (MOCA). The MOCA is a clinician-administered tool with scores ranging from 0 to 30. Lower scores indicate worse cognitive function. Scores ≤ 25 are considered clinically significant. Positive change scores indicate better function with time.
• Change in Cognitive Function Scores (Month 6) [From baseline to six months post-transplant]: Cognitive function will be assessed using the Montreal Cognitive Assessment (MOCA). The MOCA is a clinician-administered tool with scores ranging from 0 to 30. Lower scores indicate worse cognitive function. Scores ≤ 25 are considered clinically significant. Positive change scores indicate better function with time.
• Change in Functional Status Scores (Month 1) [Baseline to one month post-transplant]: Functional status will be measured using the Eastern Cooperative Oncology Group (ECOG) performance scale. ECOG performance status is a single question scored on a 6-point scale (range 0 to 5) with higher scores representing greater physical restriction due to illness. Negative change scores indicate better function with time.
• Change in Functional Status Scores (Month 3) [From baseline to three months post-transplant]: Functional status will be measured using the Eastern Cooperative Oncology Group (ECOG) performance scale. ECOG performance status is a single question scored on a 6-point scale (range 0 to 5) with higher scores representing greater physical restriction due to illness. Negative change scores indicate better function with time.
• Change in Functional Status Scores (Month 6) [Baseline to six months post-transplant]: Functional status will be measured using the Eastern Cooperative Oncology Group (ECOG) performance scale. ECOG performance status is a single question scored on a 6-point scale (range 0 to 5) with higher scores representing greater physical restriction due to illness. Negative change scores indicate better function with time.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Admission to the UNC Hospital Bone Marrow Transplant Unit for allogeneic stem cell transplant
* At least 18 years of age
* Able to speak English
* Able to provide informed consent

Exclusion Criteria:

* A history of adverse reaction to IV thiamine
* Pregnancy, confirmed by a negative pregnancy test within 30 days of study enrollment

Participant flow

Outcome results

• Percentage of Participants With Delirium (Primary), Number, percentage of participants: Intervention 25; Control 21
• Delirium Severity (Secondary), Median, score on a scale: Intervention 4.0 (2.0 to 8.0); Control 4.0 (2.0 to 7.0)
• Delirium Duration (Secondary), Mean, days: Intervention 2.0 +/- 1.2; Control 4.4 +/- 4.7
• Concentration of Thiamine Status Stratified by Delirium Status (Secondary), Mean, nmol/L: Delirium 115.6 +/- 69.3; No Delirium 93.8 +/- 28.5
• Change in Health-related Quality of Life Scores (Month 1) (Secondary), Mean, score on a scale: Intervention -7.53 +/- 11.66; Control -5.69 +/- 11.59
• Change in Health-related Quality of Life Scores (Month 3) (Secondary), Mean, score on a scale: Intervention -3.96 +/- 9.11; Control -1.43 +/- 16.79
• Change in Health-related Quality of Life Scores (Month 6) (Secondary), Mean, score on a scale: Intervention -4.36 +/- 14.09; Control 0.28 +/- 12.17
• Change in Depression Scores (Month 1) (Secondary), Mean, T-score: Intervention -1.34 +/- 8.28; Control 1.16 +/- 6.12
• Change in Depression Scores (Month 3) (Secondary), Mean, T-score: Intervention 0.93 +/- 6.24; Control 0.32 +/- 9.53
• Change in Depression Scores (Month 6) (Secondary), Mean, T-score: Intervention 0.14 +/- 6.88; Control -1.66 +/- 7.89
• Change in Post-traumatic Stress Symptom Scores (Month 1) (Secondary), Mean, score on a scale: Intervention -0.52 +/- 10.88; Control 1.55 +/- 6.92
• Change in Post-traumatic Stress Symptom Scores (Month 3) (Secondary), Mean, score on a scale: Intervention -1.50 +/- 6.58; Control 0.83 +/- 5.63
• Change in Post-traumatic Stress Symptom Scores (Month 6) (Secondary), Mean, score on a scale: Intervention 1.79 +/- 9.14; Control 1.32 +/- 7.00
• Change in Cognitive Function Scores (Month 1) (Secondary), Mean, score on a scale: Intervention -0.70 +/- 3.35; Control -0.09 +/- 2.76
• Change in Cognitive Function Scores (Month 3) (Secondary), Mean, score on a scale: Intervention -0.12 +/- 0.97; Control 0.97 +/- 2.82
• Change in Cognitive Function Scores (Month 6) (Secondary), Mean, score on a scale: Intervention 0.71 +/- 3.32; Control 1.54 +/- 2.87
• Change in Functional Status Scores (Month 1) (Secondary), Mean, score on a scale: Intervention 0.70 +/- 0.67; Control 0.88 +/- 0.93
• Change in Functional Status Scores (Month 3) (Secondary), Mean, score on a scale: Intervention 0.69 +/- 0.62; Control 0.60 +/- 0.89
• Change in Functional Status Scores (Month 6) (Secondary), Mean, score on a scale: Intervention 0.46 +/- 0.93; Control 0.21 +/- 0.63

Adverse events

Time frame: Adverse event (AE) data were only collected from October 2017 through February 2020, during the intervention phase of the study and coinciding with participants' hospitalization for hematopoietic stem cell transplantation. This phase lasted up to 30 days for each participant. The study was completed on August 10, 2020, as secondary outcomes were collected for an additional 5 months after completion of AE data collection.

• Results publication: Nakamura ZM, Deal AM, Park EM, Quillen LJ, Chien SA, Stanton KE, McCabe SD, Heiling HM, Wood WA, Shea TC, Rosenstein DL. A randomized double-blind placebo-controlled trial of intravenous thiamine for prevention of delirium following allogeneic hematopoietic stem cell transplantation. J Psychosom Res. 2021 Jul;146:110503. doi: 10.1016/j.jpsychores.2021.110503. Epub 2021 Apr 27. PMID 33945982

• Study Protocol and Statistical Analysis Plan (PDF, 2020-03-26)

• Donald Rosenstein, MD, Study chair, University of North Carolina, Chapel Hill
• Zev Nakamura, MD, Principal investigator, University of North Carolina, Chapel Hill