Trial Outcomes & Findings for High Dose Intravenous Thiamine for the Prevention of Delirium in Allogeneic Hematopoietic Stem Cell Transplantation (NCT NCT03263442)

Last Updated: 2021-10-19

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

66 participants

Primary outcome timeframe

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.

Results posted on

2021-10-19

Participant Flow

Participants were recruited from the UNC Bone Marrow Transplant and Cellular Therapies Unit from October 2017 through February 2020.

Of the 66 participants who enrolled in the study, 2 withdrew prior to randomization.

Participant milestones

Participant milestones
Measure	Intervention Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Inpatient Phase STARTED	30	34
Inpatient Phase COMPLETED	28	33
Inpatient Phase NOT COMPLETED	2	1
1-month Follow-Up STARTED	28	33
1-month Follow-Up COMPLETED	27	33
1-month Follow-Up NOT COMPLETED	1	0
3-month Follow-Up STARTED	27	33
3-month Follow-Up COMPLETED	26	30
3-month Follow-Up NOT COMPLETED	1	3
6-month Follow-Up STARTED	26	30
6-month Follow-Up COMPLETED	24	28
6-month Follow-Up NOT COMPLETED	2	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Intervention Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Inpatient Phase Death	1	0
Inpatient Phase Withdrawal by Subject	1	0
Inpatient Phase Inadequate Drug Exposure	0	1
1-month Follow-Up Lost to Follow-up	1	0
3-month Follow-Up Lost to Follow-up	1	3
6-month Follow-Up Lost to Follow-up	2	2

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Intervention n=28 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days	Total n=61 Participants Total of all reporting groups
Age, Continuous	54.9 years STANDARD_DEVIATION 12.5 • n=5 Participants	53.6 years STANDARD_DEVIATION 14.7 • n=7 Participants	54.2 years STANDARD_DEVIATION 13.6 • n=5 Participants
Sex: Female, Male Female	11 Participants n=5 Participants	13 Participants n=7 Participants	24 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants	20 Participants n=7 Participants	37 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	27 Participants n=5 Participants	32 Participants n=7 Participants	59 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	3 Participants n=5 Participants	6 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	25 Participants n=5 Participants	27 Participants n=7 Participants	52 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Region of Enrollment United States	28 participants n=5 Participants	33 participants n=7 Participants	61 participants n=5 Participants
Education	14.7 years STANDARD_DEVIATION 2.7 • n=5 Participants	15.3 years STANDARD_DEVIATION 2.7 • n=7 Participants	15.0 years STANDARD_DEVIATION 2.7 • n=5 Participants
Diagnosis Acute leukemia	18 Participants n=5 Participants	19 Participants n=7 Participants	37 Participants n=5 Participants
Diagnosis Chronic leukemia	2 Participants n=5 Participants	5 Participants n=7 Participants	7 Participants n=5 Participants
Diagnosis Lymphoma	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Diagnosis Myelodysplastic Syndrome	5 Participants n=5 Participants	5 Participants n=7 Participants	10 Participants n=5 Participants
Diagnosis Myeloproliferative Disorder	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Diagnosis Other	1 Participants n=5 Participants	1 Participants n=7 Participants	2 Participants n=5 Participants
CIBMTR Disease Risk Index N/A	3 Participants n=5 Participants	3 Participants n=7 Participants	6 Participants n=5 Participants
CIBMTR Disease Risk Index low	17 Participants n=5 Participants	19 Participants n=7 Participants	36 Participants n=5 Participants
CIBMTR Disease Risk Index intermediate	3 Participants n=5 Participants	9 Participants n=7 Participants	12 Participants n=5 Participants
CIBMTR Disease Risk Index high	5 Participants n=5 Participants	2 Participants n=7 Participants	7 Participants n=5 Participants
Donor Type Matched Related Donor	9 Participants n=5 Participants	10 Participants n=7 Participants	19 Participants n=5 Participants
Donor Type Matched Unrelated Donor	16 Participants n=5 Participants	18 Participants n=7 Participants	34 Participants n=5 Participants
Donor Type Haploidentical	3 Participants n=5 Participants	5 Participants n=7 Participants	8 Participants n=5 Participants
Conditioning Regimen Myeloablative	15 Participants n=5 Participants	13 Participants n=7 Participants	28 Participants n=5 Participants
Conditioning Regimen Reduced Intensity or Non-Myeloablative	13 Participants n=5 Participants	20 Participants n=7 Participants	33 Participants n=5 Participants
ECOG Score 0	13 Participants n=5 Participants	18 Participants n=7 Participants	31 Participants n=5 Participants
ECOG Score 1	15 Participants n=5 Participants	14 Participants n=7 Participants	29 Participants n=5 Participants
ECOG Score 2	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

Population: The analysis population was defined a priori as those participants who: 1.) received at least 17 of 21 (80%) scheduled study drug doses; 2.) received at least one dose on each of the study drug administration days; and 3.) had no fewer than one DRS assessment per week until they were found to be delirious, reached 30 days post-transplant, or were discharged.

Outcome measures

Outcome measures
Measure	Intervention n=28 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Percentage of Participants With Delirium	25 percentage of participants	21 percentage of participants

SECONDARY outcome

Timeframe: 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

Population: Attrition over time is due to hospital discharge (primary reason), withdrawal, or death.

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.

Outcome measures

Outcome measures
Measure	Intervention n=28 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Delirium Severity Baseline	4.0 score on a scale Interval 2.0 to 8.0	4.0 score on a scale Interval 2.0 to 7.0
Delirium Severity Week 1	4.83 score on a scale Interval 3.0 to 9.0	4.67 score on a scale Interval 2.67 to 15.0
Delirium Severity Week 2	6.50 score on a scale Interval 2.67 to 20.33	5.33 score on a scale Interval 2.33 to 16.0
Delirium Severity Week 3	6.33 score on a scale Interval 1.0 to 18.6	5.17 score on a scale Interval 2.0 to 17.8
Delirium Severity Week 4	5.50 score on a scale Interval 4.0 to 20.0	6.00 score on a scale Interval 5.0 to 13.5
Delirium Severity Week 5	20.00 score on a scale Interval 20.0 to 20.0	7.50 score on a scale Interval 4.0 to 8.0

SECONDARY outcome

Timeframe: 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.

Population: These analyses are exclusive to those participants who experienced delirium.

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.

Outcome measures

Outcome measures
Measure	Intervention n=7 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=7 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Delirium Duration	2.0 days Standard Deviation 1.2	4.4 days Standard Deviation 4.7

SECONDARY outcome

Timeframe: 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

Population: Only those participants in whom thiamine levels were obtained at the end of the seven day administration were included.

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.

Outcome measures

Outcome measures
Measure	Intervention n=14 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=45 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Concentration of Thiamine Status Stratified by Delirium Status	115.6 nmol/L Standard Deviation 69.3	93.8 nmol/L Standard Deviation 28.5

SECONDARY outcome

Timeframe: From baseline to one month post-transplant

Population: Participants who completed the 1 month follow-up period.

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.

Outcome measures

Outcome measures
Measure	Intervention n=27 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Health-related Quality of Life Scores (Month 1)	-7.53 score on a scale Standard Deviation 11.66	-5.69 score on a scale Standard Deviation 11.59

SECONDARY outcome

Timeframe: Baseline to three months post-transplant

Population: Participants who completed the 3 month follow-up period

Outcome measures

Outcome measures
Measure	Intervention n=26 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=30 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Health-related Quality of Life Scores (Month 3)	-3.96 score on a scale Standard Deviation 9.11	-1.43 score on a scale Standard Deviation 16.79

SECONDARY outcome

Timeframe: Baseline to six months post-transplant

Population: Participants who completed the 6 month follow-up period

Outcome measures

Outcome measures
Measure	Intervention n=24 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=28 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Health-related Quality of Life Scores (Month 6)	-4.36 score on a scale Standard Deviation 14.09	0.28 score on a scale Standard Deviation 12.17

SECONDARY outcome

Timeframe: Baseline to one month post-transplant

Population: Participants who completed the 1 month follow-up period.

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.

Outcome measures

Outcome measures
Measure	Intervention n=27 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Depression Scores (Month 1)	-1.34 T-score Standard Deviation 8.28	1.16 T-score Standard Deviation 6.12

SECONDARY outcome

Timeframe: Baseline to three months post-transplant

Population: Participants who completed the 3 month follow-up period

Outcome measures

Outcome measures
Measure	Intervention n=26 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=30 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Depression Scores (Month 3)	0.93 T-score Standard Deviation 6.24	0.32 T-score Standard Deviation 9.53

SECONDARY outcome

Timeframe: Baseline to six months post-transplant

Population: Participants who completed the 6 month follow-up period

Outcome measures

Outcome measures
Measure	Intervention n=24 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=28 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Depression Scores (Month 6)	0.14 T-score Standard Deviation 6.88	-1.66 T-score Standard Deviation 7.89

SECONDARY outcome

Timeframe: Baseline to one month post-transplant

Population: Participants who completed the 1 month follow-up period.

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.

Outcome measures

Outcome measures
Measure	Intervention n=27 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Post-traumatic Stress Symptom Scores (Month 1)	-0.52 score on a scale Standard Deviation 10.88	1.55 score on a scale Standard Deviation 6.92

SECONDARY outcome

Timeframe: Baseline to three months post-transplant

Population: Participants who completed the 3 month follow-up period

Outcome measures

Outcome measures
Measure	Intervention n=26 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=30 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Post-traumatic Stress Symptom Scores (Month 3)	-1.50 score on a scale Standard Deviation 6.58	0.83 score on a scale Standard Deviation 5.63

SECONDARY outcome

Timeframe: Baseline to six months post-transplant

Population: Participants who completed the 6 month follow-up period.

Outcome measures

Outcome measures
Measure	Intervention n=24 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=28 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Post-traumatic Stress Symptom Scores (Month 6)	1.79 score on a scale Standard Deviation 9.14	1.32 score on a scale Standard Deviation 7.00

SECONDARY outcome

Timeframe: From baseline to one month post-transplant

Population: One participant in the control arm was unable to complete the MoCA due to restrictions on in-person human subjects research during the COVID-19 pandemic. Otherwise, all participants available at the 1-month follow-up time point were included.

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.

Outcome measures

Outcome measures
Measure	Intervention n=27 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=32 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Cognitive Function Scores (Month 1)	-0.70 score on a scale Standard Deviation 3.35	-0.09 score on a scale Standard Deviation 2.76

SECONDARY outcome

Timeframe: Baseline to three months post-transplant

Population: Participants who completed the 3 month follow-up period and we able to participate in the cognitive assessment. Of the 26 participants active in the thiamine arm at the 3 month follow-up, 1 did not complete this measure due to barriers related to the COVID-19 pandemic.

Outcome measures

Outcome measures
Measure	Intervention n=25 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=30 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Cognitive Function Scores (Month 3)	-0.12 score on a scale Standard Deviation 0.97	0.97 score on a scale Standard Deviation 2.82

SECONDARY outcome

Timeframe: From baseline to six months post-transplant

Population: Participants who completed the 6 month follow-up period.

Outcome measures

Outcome measures
Measure	Intervention n=24 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=28 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Cognitive Function Scores (Month 6)	0.71 score on a scale Standard Deviation 3.32	1.54 score on a scale Standard Deviation 2.87

SECONDARY outcome

Timeframe: Baseline to one month post-transplant

Population: Participants who completed the 1 month follow-up period

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.

Outcome measures

Outcome measures
Measure	Intervention n=27 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=33 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Functional Status Scores (Month 1)	0.70 score on a scale Standard Deviation 0.67	0.88 score on a scale Standard Deviation 0.93

SECONDARY outcome

Timeframe: From baseline to three months post-transplant

Population: Participants who completed the 3 month follow-up.

Outcome measures

Outcome measures
Measure	Intervention n=26 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=30 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Functional Status Scores (Month 3)	0.69 score on a scale Standard Deviation 0.62	0.60 score on a scale Standard Deviation 0.89

SECONDARY outcome

Timeframe: Baseline to six months post-transplant

Population: Participants who completed the 6 month follow-up period.

Outcome measures

Outcome measures
Measure	Intervention n=24 Participants Thiamine 200 mg IV Thiamine: 200 mg IV three times daily for seven days	Control n=28 Participants Normal saline IV Normal saline: Normal saline IV three times daily for seven days
Change in Functional Status Scores (Month 6)	0.46 score on a scale Standard Deviation 0.93	0.21 score on a scale Standard Deviation 0.63

Adverse Events

Intervention

Serious events: 0 serious events

Other events: 0 other events

Deaths: 1 deaths

Control

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Adverse event data not reported

Additional Information

Zev Nakamura

University of North Carolina - Chapel Hill

Phone: 984-974-3829

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place