Clinical trial NCT06103188
Conditions: Anxiety Preoperative Anxiety
Keywords: Preoperative anxiety Anxiolytic Melatonin Diazepam Sedation Premedication
Sponsor: University of Jordan
Start date: 2023-10-02; Completion date: 2023-10-30
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The goal of this clinical trial is to compare the effect of melatonin, diazepam, and placebo on the level of anxiety in patients undergoing surgery. The main question it aims to answer is:

• Is melatonin effective in reducing the anxiety of patients undergoing surgery? Participants will be asked to answer a questionnaire then they will receive either melatonin, diazepam, or placebo, and then after an hour, they will answer the same questionnaire again.

Researchers will compare melatonin, diazepam, and placebo to see if melatonin is as effective in reducing the level of anxiety as diazepam in patients undergoing surgery.

Detailed description:
Anxiety is a tense unpleasant sensation experienced by many individuals secondary to their concerns or due to the anticipation of an unpleasant experience like a surgery. Even with the advancement of medical treatment, preoperative anxiety remains a widespread complaint that affects the patients psychologically and physically, and at the same time adversely affecting the outcome of the operation and the experience of the patient.

In this triple-blind, randomized clinical study, we aim to compare melatonin to diazepam regarding its efficacy in reducing preoperative anxiety, as well as assessing multiple other effects such as sedation, orientation, and cognition, by applying validated tools to patients undergoing elective surgeries before and after administering the premedication.

Arms: arm 1: A 5mg vitamin B12 pill arm 2: A 5mg diazepam pill arm 3: A 5mg melatonin pill
Interventions: intervention 1: Placebo intervention 2: Diazepam intervention 3: Melatonin
Intervention descriptions: intervention 1: The placebo pill will be given to the patients 1 hour prior to their planned surgery. intervention 2: Diazepam will be given to the patients 1 hour prior to their planned surgery. intervention 3: Melatonin will be given to the patients 1 hour prior to their planned surgery.

Protocol documents:
Prot_000.pdf: 
1 
 
Title page 
 
 
 
 
 
 
 
Comparing the Effect of Melatonin, Diazepam, 
and Placebo on Decreasing the Level of 
Anxiety Preoperatively 
 
NCT06103188 
 
 
Last updated: October 30, 2024 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


2 
 
Background 
Surgery carries be a heavy mental burden for the patient and can result in anxiety [1]. Preoperative 
anxiety is typically managed with benzodiazepines which have unpleasant adverse effects and can lead 
to serious complications [2,3]. 
Melatonin is a naturally occurring hormone which has shown promising results as an anxiolytic in 
both experimental and clinical studies [4-7]. Melatonin has not been associated with any serious 
adverse effects [8], and the known adverse effects are dizziness, headache, nausea, and fatigue. 
Melatonin could potentially be an effective anxiolytic drug for treating perioperative anxiety [9]. 
 
Objective 
To investigate the effect of oral melatonin as a preoperative anxiolytic. 
 
Study design 
This study is a prospective, randomized, triple-blinded, placebo-controlled clinical trial conducted at 
the Jordan University Hospital. Participants will be recruited from patients undergoing various elective 
surgeries at the Jordan University Hospital. Participants will be selected based on predefined inclusion 
and exclusion criteria. 
 
Participants 
Inclusion criteria: 
- 
Patients with ASA grade 1 or 2 
- 
Age between 18 to 60 
- 
Posted for general anesthesia 
Exclusion criteria: 
- 
Patients with a known allergy to any of the drugs under study 
- 
Pregnancy 
- 
Illiteracy 
- 
Patients with any mental illness 
- 
Patients currently taking antipsychotics or antidepressants 
Withdrawal and drop-out-criteria 
1. 
If the participant wishes to withdraw from the trial at any timepoint. 
2. 
If the participant suffers from any treatment complication the results in a reoperation or 
admission to an intensive care unit. 


3 
 
 
3. 
If circumstances not covered by criteria 1-2 occur and the investigator deems it necessary 
regarding the health of the participant. 
  
Study course 
Patients will be approached in the anesthesia clinic and provided with detailed information about the 
study. Contact information about the participants will be collected for future follow-up if needed. 
Patients are given written and verbal information about the purpose and conduct of the study and are 
required to give written and verbal consent to participate. 
Participants will be contacted again in the holding clinic 120 minutes prior to their scheduled surgery. 
They will be asked to complete a questionnaire assessing their anxiety, sedation, and orientation. 
 
Following the baseline assessment, participants will be administered oral 5 mg melatonin, 5 mg 
diazepam, or an identical placebo. The same variables (anxiety, sedation, and orientation) will be 
reassessed after 60 minutes. Any intraoperative or postoperative events will be recorded by the 
corresponding anesthesiologist. 
 
Anxiety will be measured using both the Amsterdam Preoperative Anxiety and Information Scale 
(APAIS) [10] and visual analogue scales (VAS). Sedation will be measured using Ramsay sedation 
scale [11], and orientation to time and place was assessed. 
 
Randomization 
Medications were packaged in identical containers and labeled by an independent investigator. 
Randomization was conducted using Microsoft Excel (Microsoft Corporation, 2021) VBA scripting, 
which assigned treatments and patient codes independently. The script ensured equitable distribution 
of treatments across genders. 
Furthermore, the patients' identity was safeguarded through the utilization of unique fake IDs. 
Participants are randomized at a ratio of 1:1:1. The investigators and data analysts are not aware of the 
content of the containers. An identification key is stored in sealed envelopes. 
 
 
 
 


4 
 
OUTCOMES 
Primary outcome 1: 
 
Title: Change in the anxiety score based on VAS 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
VAS (Visual Analogue Score) Anxiety Scale is a 100 mm long scale. The scale is marked in 
millimeters from 0 to 100, where 0 correlates with no anxiety at all, and 100 correlates to anxiety as 
bad as possible. The maximum score is 100 and minimum 0. The patient is asked to point on the scale 
according to his anxiety level. The more the reduction in anxiety from baseline, the better the 
outcome. 
 
Primary outcome 2: 
Title: Change in anxiety score based on The Amsterdam Preoperative Anxiety and Information 
Scale (APAIS) 
Time frame: Before administration of pre-medication, and after 1 hour from the administration 
of premedication. 
Description: 
The Amsterdam Preoperative Anxiety and Information Scale (APAIS) is a self-reported questionnaire. 
The scale consists of six items, four of which assess the patient’s anxiety, while the last two assess the 
patients’ need-for-information and the patient must choose how much he agrees with each item on a 
scale of 1 (not at all) to 5 (very much). The more the reduction in the anxiety score from baseline the 
better the outcome. 
 
Secondary outcome 1: 
Title: Change in sedation 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
Sedation will be assessed with Ramsay sedation scale (RSS) as follows: 
1 – Patient is anxious and agitated or restless, or both 
2 – Patient is cooperative, oriented, and tranquil 
3 – Patient responds to commands only 
4 – Patient exhibits brisk response to light glabellar tap or loud auditory stimulus 
5 – Patient exhibits a sluggish response to light glabellar tap or loud auditory stimulus 


5 
 
6 – Patient exhibits no response. 
Secondary outcome 2: 
Title: Change in orientation 
Time frame: Before pre-medication, and after 1 hour from the administration of the premedication. 
Description: 
Orientation will be assessed with a three-point scale as follows: 
0 – None 
1 – Orientation in either time or place 
2 – Orientation in both 
REFERENCER 
1. 
Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The visual analog scale allows 
effective measurement of preoperative anxiety and detection of patients' anesthetic concerns. Anesth 
Analg 2000; 90: 706-12. 
 
2. 
Klein M, Gögenur I, Rosenberg J. Postoperative non-steroidal anti-inflammatory drugs 
increase anastomotic leakage rate after colorectal resection. BMJ 2012; 345: e6166. 
 
3. 
Kehlet H, Wilmore DW. Evidence-based surgical care and the evolution of fast-track surgery. 
Ann Surg 2008; 248: 189-98. 
4. 
Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin 
as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of 
randomized 
trials. Anaesthesiology 2010; 113: 968-76. 
 
5. 
Andersen LP, Werner MU, Rosenberg J, Gögenur I. A systematic review of peri-operative 
melatonin. Anaesthesia 2014; 69: 1163-71. 
 
6. 
Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and 
clonidine on postoperative pain and morphine comsumption in patients undergoing abdominal 
hysterectomy; a double- blind, randomized, placebo-controlled study. J Pain 2009; 10: 100-8. 
 
7. 
Caumo W, Torres F, Moreira NL, Jr., Auzani JA, Monteiro CA, Londero G, Rbeiro DF, 
Hidalgo MP. The clinical impact of preoperative melatonin in postoperative outcomes in patients 
undergoing abdominal hysterectomy. Anesth Analg 2007; 105: 1263-71. 


6 
 
 
8. 
Nordlund JJ, Lerner AB. The effects of oral melatonin on skin color and on the release of 
pituitary hormones. J Clin Endocrinol Metab 1977; 45: 768-74. 
 
9. 
Andersen LP, Gögenur I, Rosenberg J, Reiter RJ. The safety of melatonin in humans. Clin 
Drug Investig 2016; 36 :169-75. 
 
10. 
Moerman N, van Dam FS, Muller MJ, Oosting H. The Amsterdam Preoperative Anxiety and 
Information Scale (APAIS). Anesth Analg. 1996 Mar;82(3):445-51. doi: 10.1097/00000539-
199603000-00002 
 
11. 
Dawson R, von Fintel N, Nairn S. Sedation assessment using the Ramsay scale. Emerg Nurse. 
2010 Jun;18(3):18-20. doi: 10.7748/en2010.06.18.3.18.c7825. PMID: 20608397. 
 
 

SAP_001.pdf: 
Comparing Melatonin to Diazepam as a 
Premedication: a Triple-blind, Randomized, 
Placebo Controlled Clinical Trial 
 
NCT06103188 
30/10/2024 


Statistical Analysis Plan (SAP) 
Benzodiazepines vs Melatonin for Preoperative Anxiety: A randomized 
controlled trial 
 
 
 
 
 
Principal Investigator 
Omar Ismail 
Student 
University of Jordan, Amman, Jordan 
Sponsor: 
Jordan University Hospital 
 
 
 
 
 
Authors 
Karam Albdour 
Student 
University of Jordan, Amman, Jordan 
 
 
Kamel Jaber 
Student 
University of Jordan, Amman, Jordan 
 
 
Version 
Draft 1.0 


 
SIGNATURE PAGE 
 
 
 
Principal Investigator 
 
Omar Ismail (15/09/2023) 
 
 
 
 
 
 
 
 
Authors 
 
 
Karam Albdour (15/09/2023) 
 
 
 
 
 
Kamel Jaber (15/09/2023) 


Abbreviations 
VAAS: Visual Analogue Anxiety Scale 
ASA: American Society of Anesthesiologists 
APAIS: Amsterdam Preoperative Anxiety and Information Scale 
RSS: Ramsay Sedation Scale 
DSST: Digital symbol substitution test 
CI: Confidence Interval 
IQR: Interquartile range 
SD: Standard Deviation 
ANOVA: Analysis of Variance 


 
 
1. Study Overview 
 
The primary objective of this triple-blind, randomized clinical study, is to conduct a comparative 
analysis of the impact of melatonin, diazepam, and placebo on anxiety levels in patients 
undergoing surgical procedures. This study aims to address the research question: 
Does melatonin demonstrate efficacy in reducing anxiety among patients undergoing surgery? 
Participants will be asked to complete a questionnaire, after which they will be administered 
melatonin, diazepam, or placebo. One hour later, they will be asked to complete the same 
questionnaire again. Researchers will compare melatonin, diazepam, and placebo to determine if 
melatonin is as effective as diazepam in reducing the level of anxiety in patients undergoing 
surgery 
 
 
2. Study design 
This study is a prospective, randomized, triple-blinded, placebo-controlled clinical trial conducted 
at the Jordan University Hospital. Participants will be recruited from patients undergoing various 
elective surgeries at the Jordan University Hospital. Participants will be selected based on 
predefined inclusion and exclusion criteria as follows: 
Inclusion criteria: 
- 
Patients with ASA grade 1 or 2 
- 
Age between 18 to 60 
- 
Posted for general anesthesia 
Exclusion criteria: 
- 
Patients with a known allergy to any of the drugs under study 
- 
Pregnancy 
- 
Illiteracy 
- 
Patients with any mental illness 
- 
Patients currently taking antipsychotics or antidepressants 
Patients will be approached in the anesthesia clinic and provided with detailed information about 
the study. Those who are willing to participate will provide written informed consent. Contact 
information of the participants will be collected for future follow up if needed. Patients will be 
contacted in the holding clinic 120 minutes prior to their scheduled surgery. They will be asked to 
complete a questionnaire assessing their anxiety, sedation, and orientation. 
Following the baseline assessment, the assigned medication will be administered to each patient. 
The same variables (anxiety, sedation, and orientation) will be reassessed after 60 minutes. Any 
intraoperative or postoperative events will be recorded by the corresponding anesthesiologist. 


2.1 Randomization and blinding 
To ensure robustness in participant assignment and minimize potential biases, a triple-blind 
design was adopted. This involved concealing the treatment assignments not only from the 
participants and researchers but also from those responsible for administering the treatments and 
collecting the responses. The study's sample comprised 87 participants, evenly distributed across 
three groups of 29 each. 
Randomization was conducted using Excel VBA scripting, which assigned treatments and patient 
codes independently. The script ensured equitable distribution of treatments across genders. 
Furthermore, the patients' identity was safeguarded through the utilization of unique fake IDs. 
2.2 Sample size calculation 
In order to achieve an alpha error probability of 0.05, and power of 0.9, power analysis was 
conducted using G*Power 3.1.9.7. The literature reports the smallest effect size as f = 1, with a 
convention that considers effect sizes greater than 0.4 as strong. To detect even more subtle effects 
(f = 0.5) with an alpha-error of 0.01 and a power of 0.9, a sample size of 75, divided into 3 groups, 
was required, and to account for possible dropouts we decided on 87 as the total sample size with 
29 participants in each arm. 
 
3. General Analysis Considerations 
3.1 Timing of Analysis 
The primary analysis will be conducted after the completion of data collection, which is 
anticipated to be in August 2023. No interim analysis is applicable 
3.2 Analysis Populations 
3.2.1 Full Analysis Population 
The Full Analysis Population, also known as the Intention to Treat population, will include all 
randomized participants who received their assigned medication, and completed both pre- and 
post-administration assessments. Missing data will be handled as described in section 3.4 
3.2.2 Per Protocol Population 
The per-protocol population will include all participants who received the assigned medication 
and completed both pre- and post-administration assessments. Any subjects with missing data 
will be excluded from this population. 
3.2.3 Safety Population 
The Safety Population will comprise all participants who received at least one dose of the study 
medication (Full analysis population). Safety outcomes and adverse events will be analyzed in 
this population. 
3.3 Multi-center studies 
N/A 


 
3.4 Missing Data 
The statistical analysis plan will employ a complete case analysis approach, whereby cases with 
missing data will be excluded from the primary analysis. To ensure the validity of the findings, 
efforts will be made to minimize missing data during the study, and any instances of missing data 
will be thoroughly documented. Anticipated missing data is expected to be minimal. However, if 
the proportion of missing data exceeds 20%, sensitivity analyses will be conducted to assess the 
potential impact on the study outcomes. Given the expectation of minimal missing data, the use 
of additional methods such as multiple imputation is considered unnecessary. 
3.5 Interim Analysis 
N/A 
3.6 Multiple testing 
If significant differences are found among the study arms, post hoc analysis will be utilized to 
reveal which groups actually differ from one another. This multiple comparison testing will 
increase the type 1 error, and thus, correction of alpha using the Tukey's test will be employed to 
reduce the rate of false positives. This would reduce the power of analysis and increase the type 2 
error, but as a conservative safety approach, it’s considered superior. 
 
 
4 Summary of Study Data 
The summary of the data will be presented according to the nature and distribution of the 
variables. Normally distributed continuous data will be reported using the following statistics: 
number of observations, mean, standard deviation (SD), minimum, and maximum. Non-normally 
distributed continuous data will include: number of observations, median, and IQR unless 
specified otherwise. Categorical data will be summarized by providing the count and percentage 
of patients in each category. 
Summary statistics will be reported with an appropriate level of precision. Mean, SD, median, 
and IQR will be reported with an additional decimal place compared to the original data. The 
95% confidence interval (CI) will be reported to two decimal places. Minimum and maximum 
values will be reported with the same number of significant figures as the original data. In 
frequency tables, percentages will be presented with one decimal place, which p-values will be 
reported up to 3 decimal places or displayed as <0.001. 
In all summary tables, the structure will be organized to include a column for each treatment arm. 
Each table will be appropriately annotated to indicate the total population size relevant to that 
specific table and treatment, taking into account any missing observations. 
4.1 Derived variables 
N/A 


4.2 Protocol Deviations 
Major deviations: Participants who undergo the baseline assessment, receive their assigned 
medication but subsequently decline to complete the post-medication assessment. In the full 
analysis population, these participants will be included; however, they will be excluded from the 
per-protocol analysis. 
4.3 Demographic and Baseline Variables 
Demographic variables include: Participants’ age and gender. 
Baseline variables include: Visual analogue score (VAS) Anxiety scale, The Amsterdam 
Preoperative Anxiety and Information Scale (APAIS), the Ramsay Sedation scale (RSS), and 
orientation. The summary statistics will be produced in accordance with Section 3. 
4.4 Treatment Compliance 
N/A 
 
 
5 Efficacy Analysis 
The summary statistics will be produced in accordance with Section 3. Differences in baseline 
variables among treatment arms will be assessed using one-way ANOVA or the corresponding 
non-parametric test. All efficacy analyses will be based on the full analysis population as this 
approach is considered more conservative and prevents overestimation of the effects. However, 
Per protocol analysis will be used for sensitivity analysis as needed. 
5.1 Primary Efficacy Analyses 
Continuous primary outcomes, such as the changes in the Amsterdam Preoperative Anxiety and 
Information Scale (APAIS) and the Visual Analogue Anxiety Scale (VAAS), will be reported as 
the mean difference. The statistical analysis will involve computing p-values to compare the 
mean difference among the three treatment arms. This comparison will be conducted using either 
one-way analysis of variance (ANOVA) or the corresponding non-parametric test (e.g.Kruskal 
Wallis test), as appropriate. 
5.2 Secondary Efficacy Analyses 
Continuous primary outcomes, such as the changes in sedation level will be reported as the mean 
difference. The statistical analysis will involve computing p-values to compare the mean 
difference among the three treatment arms. This comparison will be conducted using either one- 
way analysis of variance (ANOVA) or the corresponding non-parametric test (e.g.Kruskal Wallis 
test) as appropriate. 
Categorical secondary outcomes, such as changes in orientation, will be evaluated using statistical 
tests to determine if there are significant differences among the three treatment arms. The chi- 
square test of independence or Fisher's exact test will be employed to assess these differences and 
identify any statistically significant results. 


5.3 Post Hoc Analysis 
In the case of statistically significant findings, post-hoc testing will be conducted using Tukey- 
Kramer Test. This additional analysis aims to further explore and characterize the specific group 
differences observed. 
5.4 Subgroup Analysis 
To assess for any differences in the response between both genders, subgroup analysis using the 
participants’ genders will be conducted using independent samples t-test for each study arm if the 
one-way ANOVA proved significant, or for the whole sample if no significant differences were 
found between the study arms. 
5.5 Sensitivity Analysis 
Not applicable 
 
 
6 Statistical Analysis Software 
All statistical analysis and summaries will be carried out on IBM SPSS statistics V29. Software R 
4.2.2 will be used for drawing plots where applicable