Clinical trial NCT04272606
Conditions: Degenerative Disc Disease
Keywords: Posterior Lumbar Interbody Fusion Transforaminal Lumbar Interbody Fusion Tranexamic Acid Neurosurgery Delirium
Sponsor: Catherine R. Olinger
Start date: 2020-08-01; Completion date: 2023-06-12
Enrollment: 123 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Tranexamic acid and placebo will be given during surgery to patients who have elected to undergo lumber interbody fusion on 2 or more levels. Information regarding blood loss, transfusions needed, postoperative cognitive status (including delirium), postoperative markers of systemic inflammation and duration of hospital stay will be collected.

Detailed description:
This study is to assess whether tranexamic acid (a drug that is used to coagulate the blood and reduce bleeding) use in lumbar spinal fusion can reduce blood loss and postoperative delirium compared to placebo. Thusly reducing need for transfusion, shorting the hospital stay and improving outcomes. For this the study will randomize patients who are receiving elective lumbar interbody fusion (PLIF or TLIF) of 2 or more levels for degenerative disc disease (DDD) into 2 groups. Group 1 would receive tranexamic acid during the surgery while group 2 will receive placebo. Blood loss during the surgery and postoperatively (while the patient has a drain) will be monitored along with the amount of transfusions needed, postoperative cognitive status (including delirium), postoperative markers of systemic inflammation, and and the duration of hospital stay. Delirium occurrence and severity will be assessed daily for the first 5 days after surgery or at discharge, whichever comes first. Cognitive status (neuropsychological tests) will be assessed at post-discharge follow up visits and compared to preoperative status.

The drug or placebo are only given during the surgery. The patient population includes elective cases of patient undergoing lumbar spinal fusion of 2 or more levels. Spinal fusions are known to be associated with blood loss, especially when the surgeries are long and more levels need to be fused.

Arms: arm 1: 1:1 randomization, given tranexamic acid during surgery, visual acuity exam arm 2: 1:1 randomization, given standard of care treatment during surgery, visual acuity exam
Interventions: intervention 1: Tranexamic Acid intervention 2: Saline Solution intervention 3: Visual Acuity Exam intervention 4: 3 Minute Diagnostic Interview for Confusion Assessment Method (3D-CAM)
Intervention descriptions: intervention 1: Antifibrinolytic Agent intervention 2: Placebo intervention 3: Supplemented into standard of care daily neurological exam on day of surgery and day after intervention 4: 3D-CAM is a brief verbal assessment tool that can be used to test patients and study patients for delirium.

Protocol documents:
Prot_002.pdf: 
Cover Page for Study Protocol 
 
 
Sponsor-Investigator: 
Catherine R. Olinger 
NCT Number: 
NCT04272606 
Unique Protocol ID: 
201912099 
Official Title: 
Prospective, Randomized, Double 
Blind Study on the Effects of 
Tranexamic Acid on Intraoperative 
Blood Loss During Lumbar Spinal 
Fusion And Instrumentation 
Date of Document: 
21 March 2022 
 


Version 3    21 March 2022 
 
Prospective, randomized, double blind study on the effects of tranexamic acid on 
intraoperative blood loss during lumbar spinal fusion and instrumentation 
Woodroffe, Ray, Gold, Park, Igram, Hiroyuki, Yamagushi, Kawasaki, Oya, Olinger, 
Hitchon, Howard 
 
Primary Aim of this proposal is to demonstrate that tranexamic acid (TXA) reduces intraoperative 
blood loss and transfusion requirements during and following posterior lumbar spinal fusions  
Primary Hypothesis: 
TXA reduces intraoperative and postoperative (up to 7 days) blood loss and transfusion 
requirements.   
 
Primary Objective: 
1. To test the effect of TXA on the need for red blood cell (RBC) transfusion (intraoperatively 
and postoperatively) in patients undergoing lumbar spinal fusion compared to placebo (Normal 
Saline). This will be adjusted for number of levels to fuse, duration of surgery and patient’s 
weight. 
2. To test the effect of TXA on blood loss adjusted for weight, duration and number of level fused 
 
Secondary Objectives: 
1. To test the effect of TXA on the following: 
a. Duration of surgery (Skin to skin) 
b. Length of hospitalization (LOH) 
c. Cost/effectiveness analysis 
2. To assess the safety of TXA. 
 
Exploratory objectives: 
 
1. To test the effect of TXA on the required duration of subcutaneous drain placement (Hemovac) 
2. To assess the effect of TXA on incidence of postoperative delirium.  
 
 
Study Design: 
Phase 2B randomized, single-center, double-blinded, placebo vs. TXA clinical trial with 1:1 
randomization.  
Primary endpoints: 
1. The amount of RBC transfusion intraoperatively 
2. The amount of RBC transfusion up to 7 days postoperatively 
3. Measurement of intraoperative blood loss, postoperative blood loss, and total blood loss. 
 
Secondary endpoints: 
1. Safety analysis: thromboembolic events and worsening renal function in TXA vs placebo 
2. LOH 


Version 3    21 March 2022 
 
3. Cost effectiveness analysis: cost saving from reduction in transfusion and LOH vs. cost of 
TXA administration 
 
Exploratory endpoints: 
1. Duration of drain in place 
2. Postop wound complication incidence 
3. Incidence of postoperative delirium based on CAM-3D and CAM-ICU delirium screening 
tools.  
4. Effect of delirium on cognitive function.  
 
Intervention: 
An intravenous infusion of 10mg/kg of TXA (Amchafibrin VR 500mg; Rottapharm S.L., 5-mL 
vials) is administered for 20min before the surgical incision, followed by perfusion of 2mg/kg/h 
up to surgical wound closure at completion of surgery vs. a saline solution (placebo) administered 
according to the same infusion pattern and timing as in the TXA. 
 
Drug: TXA is a synthetic reversible competitive inhibitor to the lysine receptor found on 
plasminogen. The binding of this receptor prevents plasmin (activated form of plasminogen) from 
binding to and ultimately stabilizing the fibrin matrix. TXA used for hereditary angioedema works 
by its indirect effect of reducing complement activation. By reducing plasmin activity, it reduces 
the consumption of C1 esterase inhibitor. The half-life of TXA is 2 to 11 hours. The duration of 
action is 3 hours after the initial dose. 
Dose: 10mg/Kg bolus 20 min prior to infusion followed by 2mg/kg/h up to closure 
Protocol: 
 
Patients of ages 18 to 90 years old with ASA class I-IV undergoing elective lumbar interbody 
fusion (PLIF or TLIF) for degenerative disc disease (DDD) are considered eligible for inclusion 
in this study. Patients are screened for the inclusion/exclusion criteria below. Patients will enroll 


Version 3    21 March 2022 
 
in the study at the time of signing consent for surgery at their preoperative visit. Participation in 
the study has no bearing on their consent for surgery. After the patient signs consent at the 
preoperative visit, they will complete the baseline cognitive assessment (TICS-m, COWAT, TMT, 
BDI, 3D-CAM). Patients will have from the first visit until the day of surgery to withdraw from 
the study (2-6 weeks) and from the first visit to the preop visit to consent (1-4 weeks). Once 
patients are consented, they are considered enrolled. Patients can withdraw out of the study at any 
time prior to surgery. Once they withdraw, they will no longer be considered participants in the 
study. Patients will be randomized (blind randomization) using SPSS to placebo vs TXA. The 
primary surgeon, anesthesia care provider, investigator, and outcomes assessor will be blinded to 
the treatment and control arms. The intraoperative estimated blood loss in milliliters will be 
recorded routinely by the anesthesiologist participating in the case. All patients will be discharged 
to the neurosurgical or orthopedics wards postoperatively. Twice daily (~8am and ~4pm) a study 
member will administer the 3D-CAM or CAM-ICU delirium screening assessments to determine 
delirium status. Patients are followed until their second postoperative visit to clinic, approximately 
3 months after the surgery. At the first visit, patients will be screened for any adverse events. At 
both the first and second visit postoperatively, the patients will complete the cognitive testing 
(TICS-m, COWAT, TMT, BDI, 3D-CAM).  
  
Baseline Demographics/Data 
Age 
Chronic Liver Disease 
Sex 
History of DVT, PE, TEE 
Height 
Oral anticoagulation (and reason for it) 
Weight 
Oral antiplatelet therapy (and reason for 
it) 
BMI 
Visual impairment 
Smoking (Yes/No) 
Number of levels fused 
DM  
Number of Interbody fused 
Coronary Artery Disease 
ASA classification 
Peripheral Vascular Disease 
OB/GYN: 
breast 
feeding, 
OCP 
or 
pregnant 


Version 3    21 March 2022 
 
 
 
 
 
 
 
Inclusion Criteria 
1) Age 18-90 years 
2) ASIA anesthesia risk of I to IV 
3) Patients undergoing posterior lumbar spinal fusion for DDD.  
4) Patients have failed conservative management, which include PT/OT and/or injections. 
 
Exclusion:  
1) ASIA class V 
2) Patient unable to consent 
3) Patient with chronic kidney disease stage III or above: baseline plasma creatinine>1.5mg/dL 
4) Patient with known liver failure 
5) Patients on anticoagulation or dual antiplatelets (presence of vascular stents). 
6) Patients with artificial valves. 
7) Patients with allergy to TXA 
8) Patients with platelet count < 150 000  
9) Patients with PT>15s 
10) Patients with APPT>38s 
11) History of stroke or (an) unprovoked thromboembolic event(s). 
12) History of intracranial bleeding, 
13) Pregnancy 
14) known defective color vision 
15) history of venous or arterial thromboembolism or active thromboembolic disease 
16) Patients with severe pulmonary or cardiac disease. 
17) Patients who refuse transfusion of blood products 
18) Patients with chronic anemia with Hg<8 
19) Patients undergoing lumbar fusion for disease other than DDD (neoplasm) 
20) Patients undergoing lumbar fusion by anterior or lateral approach. 
21) Minimally invasive TLIF are excluded. 
22) Emergent cases. 
23) Women on hormonal contraception 
24) Retinal vein or artery occlusion 
25) Hypercoagulability 
26) Seizure disorder 
27) Current use of tretinoin 
28) Current use of chlorpromazine 
29) Breast feeding 
 
Chronic Kidney Disease 
Chronic anemia (Hb<8) 


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Variables 
Preop 
Hospitalization 
6-week f/u  
3-month f/u 
Demographics 
X 
 
 
  
BHCG 
 
 
 
LFT * 
X 
Coags (PTT/PT/INR) 
X 
GFR 
X 
POD1 
 
SF Rand/ PROMIS 
X 
X 
                             X  
CBC 
X 
X 
 
Complications 
(DVT,PE,SSI,TE) 
 
X 
X 
Visual testing * 
X 
POD1 
New deficit 
POD1 
 
X 
Intraop 
1h 
postop 
(PACU) 
POD1,2,3 
 
Drain output/duration 
X 
Blood Loss 
X 
3D-CAM/CAM ICU* 
X 
X 
X 
X 
TICS-m* 
X 
 
X 
X 


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COWAT* 
X 
 
X 
X 
TMT* 
X 
 
X 
X 
BDI* 
X 
 
X 
X 
 
 
 
 
 
Safety analysis: 
Adverse events occurring in the intraoperative period, immediate postoperative period and up to 
4-8 weeks after the procedure will be recorded. We will collect specific adverse events that might 
be related to TXA treatment, including incidence of TTE, impaired renal function (plasma 
creatinine increase>20% of baseline level), and neurological complications, such as seizures and 
vision abnormalities. Adverse events apparently unrelated to use of the drug will also be recorded. 
The plasma creatinine will be obtained on POD1 and preoperatively. Sever adverse events are 
DVT and PE. 
Sections including description of the anesthesia technique, transfusion requirements and blood 
loss, and venous thromboembolism prophylaxis are described in the Appendix. A comparison of 
the frequency and severity of adverse events occurring up to the 4-8-week follow-up period will 
be analyzed. Any SAE will be reported to the DSMB as they occur. 
 
Stopping rules or safety triggers for the study: impairment in renal function and 
thromboembolic events will trigger a meeting of the DSMB to discuss the events and decide on 
the continuation of the trial. The study will automatically be placed on hold until the investigators 
and the DSMB can conduct a review of events. All AEs will be collected, recorded, and analyzed. 
Safety oversight for this study will be provided by both the DSMB and an independent Medical 
Safety Monitor. If the rate of thromboembolic events or impaired renal function crosses the 
literature threshold or the control group with 95% probability, the study will stop. 
 
Postoperative drain management: The Hemovac drain is removed when the 8h output is <50 cc. 
The output is recorded for every 8 hour and charted. 
Indication for transfusion 
• 
Hb  <7.0 mg/dl  
• 
Anemic symptoms developed: 
• 
A decrease in blood pressure to <100 mmHg systolic, 


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• 
 tachycardia greater than 100 beats/min 
• 
Orthostatic hypotension , lightheadedness, Chest pain/palpitation, confusion (due 
to a low bp) 
• 
 Low urine output of <30 ml/h,  after initial fluid challenge with 500 ml normal saline in 
patients with a hemoglobin level between 7.0 and 8.0 mg/dl. 
 
Calculations and measurement of blood loss 
Visible blood loss = intraoperative blood loss + postoperative drainage amount; intraoperative 
blood loss = weight of liquid in the suction bottle – weight of intraoperative rinsing fluid + 
increased weight of intraoperative gauges and towers. 
Hidden blood loss is calculated based on the linear equations provided by Gross.7 The formula is 
as follows: 
1)Hidden blood loss = total blood loss before and after surgery – visible blood loss. 
2)Total blood loss before and after surgery = preoperative blood volume × (HCT difference 
before and after surgery/mean HCT before and after surgery). 
3)Preoperative blood volume = K1 × height (m)3 + K2 × body weight (kg) + K3, where K1 = 
0.3669, K2 = 0.0322, and K3 = 0.6041 in male patients, and K1 = 0.3561, K2 = 0.0331, and 
K3 = 0.1833 in female patients.8 
Outcome assessment: 
1) hemorrhage assessment:  
• 
intraoperative blood loss, 
• 
Total blood loss (Calculated) and Hidden Blood loss (Calculated) 
• 
postoperative drainage amount (per 8 h shift), 
• 
days of drain in place, HGB level (before surgery and 1, 24h, 48 and 72 hours after 
surgery), 
• 
hematocrit (HCT; same), 
• 
prothrombin time (PT), PPT before, 
• 
number of blood transfusions 
 
2) clinical efficacy evaluation: 
• 
length of hospital stay 
• 
visual analogue scale (VAS) measurement before and after surgery; duration of surgery.  
• 
SF Rand/ PROMIS preop, 6 weeks and 3 month follow-up.  
• 
Duration of the procedure 
 
3) cognitive evaluations 
• CAM-ICU/3D-CAM & 3D-CAM-S will be collected preop, during the hospitalization, and 
6 weeks and 3 month follow-up 
• TICS-m, TMT, COWAT, and BDI preop, 6 weeks and 3 month follow-up. 


Version 3    21 March 2022 
 
 
Venous thromboembolism prophylaxis 
Patients received antithrombotic prophylaxis according to the institutional guidelines and 
protocols of each participating service and the individual risk estimated by the investigator. The 
study protocol includes evaluation of the probability that a patient would experience venous 
thromboembolism (VTE) using the Wells clinical prediction guide for deep venous thrombosis 
(DVT) and pulmonary embolism (PE) or the Geneva criteria for PE. DVTs are diagnosed by using 
US and PEs by using CTA. Clinically and radiologically confirmed DVT or PE are considered 
severe adverse events. LWMH or USQH were used after 24h of the procedure (adjusted to weight 
and renal function). Patients are mobilized as early as possible with Physical and occupational 
therapy. 
 
 
Study design: 
Measures to minimize bias: randomization and blinding: Randomized block design with 
variable block sizes will be used to randomize subjects to the 2 groups with a 1:1 ratio. 
Randomization will be generated by a randomization coding software (SAS Version 9.4). 
Randomization schema will be distributed to the pharmacy and sequence numbers will be 
identified to match patient enrollment. We will use triple masking: Concealment of randomization, 
blinding of treatment (placebo and TXA are indiscernible) and blinding of data analysis. 
Unmasking will be performed at the end of the trial. We will allow for unplanned masking in case 
of severe adverse events by the DSMB. (See Adverse events section). 
 
Sample Size Determination Based on Primary Endpoint (Blood loss and transfusion)  
We are planning a study of continuous response variable from independent control and 
experimental subjects with 1:1 allocation ratio. Primary calculations are based on the mean 
difference from a meta-analysis of RCT studies between patients who received TXA and those 
who received placebo. The amount of blood loss per patient significantly decreased with TXA 
with a mean difference (MD) of 681.81 ml (95% CI: 214.49 to 1149.12 ml). The pooled weighted 
MD for blood transfusion per patient between TXA group and placebo group is −234.61 ml (95% 
CI: −383.23 to −85.99 ml). However, there was significant heterogeneity within the selected 
studies. The TXA use could decreased 44% risk of blood transfusion compared with the placebo 
group with an OR of 0.56 (95% CI: 0.36 to 0.87). Based on the previous studies, we will need to 
study 40 experimental subjects and 40 control subjects to be able to reject the null hypothesis (i.e. 
the population means of the experimental and control groups are equal) with a probability of 0.9 
(power = 90%) (Table 2). The Type I error probability associated with this test is 0.05. We will 
thus recruit 50 subjects per group and assume at least a 10% loss to follow-up. thrombosis 
complications and the use of TXA with an OR of 0.99 (95% CI: 0.06 to 16.07).  
 
 
 
Sample size calculation for Secondary endpoints: 


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1. We do not anticipate any difference in thrombosis complications as a meta-analysis showed an 
OR of 0.99 (95% CI: 0.06 to 16.07). 
2. Analyses for LOH will be based on the difference in mean hospital stay between the 2 groups. 
This will be adjusted on the number of level fused, presence of a neurological deficit, and BMI 
3. Cost effectiveness analysis: The cost of TXA has to be compared with the cost reduction from 
shorter LOH and reduction in transfusion requirements. 
Analysis of Primary End Point: 
The primary endpoint is the mean difference in total blood loss, intraoperative blood loss and 
postoperative blood loss. An ANOVA will be used to compare between the 2 groups. A type I 
error rate of 0.05 will be utilized. An exploratory GLM ANOVA will be used to test for interaction 
for the subgroups with number of level fused, BMI and duration of surgery.  
 
Analysis of Secondary End Points: 
1. LOH: LOH will be defined from the day of surgery until the patient is medically ready for 
discharge. The ‘actual LOH’ will be defined as the duration from the day of surgery to actual 
discharge. The discharge will depend on the patient insurance and facility availability. The 
‘actual LOH’ will reflect the duration of hospitalization in the general community, while the 
LOH will reflect the effect of TXA on improving the postoperative course of the patient. We 
will test for difference in mean between the 2 groups for both LOH and ‘actual LOH’. A 
multivariable linear regression model will be used to adjust for factors related to longer LOH 
such as BMI, higher ASA score preoperatively, SF-36/PROMIS, and number of level fused. 
2.  We will analyze the cost-effectiveness of TXA by computing the cost reduction from the 
decreased in transfusion and LOH and the cost increase from treating TXA related side-effects: 
additional thromboembolic complications (cost of diagnosis and treatment). We will test for 
the difference in the mean between the two groups. 
3. The other endpoints (cognitive assessments) are exploratory. 
 
 
 
 
 
References 
1. Tsutsumimoto T, Shimogata M, Ohta H, Yui M, Yoda I, Misawa H. 
Tranexamic acid reduces perioperative blood loss in cervical laminoplasty: a prospective 
randomized study. 


Version 3    21 March 2022 
 
Spine (Phila Pa 1976). 2011 Nov 1;36(23):1913-8. doi:10.1097/BRS.0b013e3181fb3a42. 
 
2. Colomina MJ1, Koo M2, Basora M3, Pizones J4, Mora L1, Bagó J5.  
Intraoperative tranexamic acid use in major spine surgery in adults: a multicentre, 
randomized, placebo-controlled trial†. Br J Anaesth. 2017 Mar 1;118(3):380-390. doi: 
10.1093/bja/aew434. 
 
3. Yuan L1, Zeng Y1, Chen ZQ1, Zhang XL1, Mai S1, Song P2, Tao LY3Efficacy and safety of 
antifibrinolytic agents in spinal surgery: a network meta-analysis. Chin Med J (Engl). 
2019 Mar 5;132(5):577-588. doi: 10.1097/CM9.0000000000000108. 
 

SAP_003.pdf: 
Cover Page for Statistical Analysis Plan 
 
 
Sponsor-Investigator: 
Catherine R. Olinger 
NCT Number: 
NCT04272606 
Unique Protocol ID: 
201912099 
Official Title: 
Prospective, Randomized, Double 
Blind Study on the Effects of 
Tranexamic Acid on Intraoperative 
Blood Loss During Lumbar Spinal 
Fusion And Instrumentation 
Date of Document: 
05 December 2023 
 


Statistical Analysis 
All analyses will be conducted using R statistical software (version 4.3.1).  Continuous variables 
will be summarized using medians and interquartile ranges and comparisons between groups will 
be done made using Wilcoxon rank sum or Kruskal-Wallis tests.  Pairwise analyses within a 
group will be made using the Wilcoxon signed rank test.  Categorical variables will be 
summarized using counts and percentages, and comparisons between groups will be performed 
using Pearson χ2 test or Fisher exact test.  Kendall’s tau (τ) will be used as a non-parametric test 
of association between variables.  For all analyses, the threshold for significance will be <0.05 
without adjustment for multiple comparisons. Variables will be compared between groups by 
calculating standardized mean differences.