Study of Hesperidin Therapy on COVID-19 Symptoms (HESPERIDIN)

• Sponsor: Montreal Heart Institute (Other)
• Overall Status: Completed
• CT.gov ID: NCT04715932
• Collaborator: Ingenew Pharmaceuticals Inc. (Other)
• Enrollment: 216
• Location: 1
• Arms: 2
• Actual Duration (Months): 3.6
• Patients Per Site Per Month: 60.3

Study Details

Study Description

Brief Summary

The main aim of this study is to determine the effects of short-term treatment with hesperidin on COVID-19 symptoms in comparison with a placebo. Treatment effects will be observed through a symptoms diary that will be completed by participants throughout the study and by taking the oral temperature daily.

Condition or Disease	Intervention/Treatment	Phase
Covid19; Anosmia; Fever; Cough; Shortness of Breath; Sore Throat; Nausea; Vomiting; Headache; Muscle Weakness; Pain, Muscle; Pain, Chest; Pain, Joint; Pain, Abdominal; Pain; Irritable Mood; Confusion	Drug: Hesperidin; Drug: Placebo	Phase 2

Detailed Description

This will be a randomized, double-blind, placebo-controlled study. The study will include subjects from Quebec diagnosed with COVID-19 infections. Following informed consent, 216 subjects meeting all inclusion and no exclusion criteria will be randomized to receive either hesperidin 1000 mg once daily (q.d.)) or placebo (1:1 allocation ratio) for 14 days. Investigational drug will be delivered to the patients' homes with an electronic oral thermometer and a symptoms diary. Follow-up phone assessments will occur after 3, 7, 10, and 14 days following randomization for evaluation of COVID-19 symptoms. Electronic Case Report Form (eCRF) will be completed by the research personnel over the phone with the patients. The symptoms diary will be mailed back to the coordinating center at the end of the study in a pre-addressed envelope.

Study Design

• Study Type: Interventional
• Actual Enrollment: 216 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 2, Randomized, Double-blind, Placebo-controlled Study of Hesperidin Therapy on COVID-19 Symptoms: The Hesperidin Coronavirus Study (Hesperidin)
• Actual Study Start Date: Feb 18, 2021
• Actual Primary Completion Date: May 25, 2021
• Actual Study Completion Date: Jun 7, 2021

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Hesperidin 1000mg Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Drug: Hesperidin; Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Placebo Comparator: Placebo 1000mg Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Drug: Placebo; Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.

Outcome Measures

Primary Outcome Measures

1. Number of Subjects With COVID-19 Symptoms at Day 3. [Day 3]

   Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 3.

2. Number of Subjects With COVID-19 Symptoms at Day 7. [Day 7]

   Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 7.

3. Number of Subjects With COVID-19 Symptoms at Day 10. [Day 10]

   Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 10.

4. Number of Subjects With COVID-19 Symptoms at Day 14. [Day 14]

   Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 14.

Secondary Outcome Measures

1. Mean Number of COVID-19 Symptoms at Day 3. [Day 3]

   Mean number of COVID-19 symptoms (range 0-13) at day 3.

2. Mean Number of COVID-19 Symptoms at Day 7. [Day 7]

   Mean number of COVID-19 symptoms (range 0-13) at day 7.

3. Mean Number of COVID-19 Symptoms at Day 10. [Day 10]

   Mean number of COVID-19 symptoms (range 0-13) at day 10.

4. Mean Number of COVID-19 Symptoms at Day 14. [Day 14]

   Mean number of COVID-19 symptoms (range 0-13) at day 14.

5. Number of Subjects With Complete Disappearance of Any Symptom. [From randomization to occurence of first event, assessed up to 14 days]

   The descriptive statistics are the number of participants having complete disappearance of any symptom.

6. Number of Subjects With the Cough Symptom. [Day 3]

   Number of subjects with the cough symptom at day 3.

7. Number of Subjects With the Cough Symptom. [Day 7]

   Number of subjects with the cough symptom at day 7.

8. Number of Subjects With the Cough Symptom. [Day 10]

   Number of subjects with the cough symptom at day 10.

9. Number of Subjects With the Cough Symptom. [Day 14]

   Number of subjects with the cough symptom at day 14.

10. Number of Subjects With the Presence of Fever. [Day 3]

    Number of subjects with the presence of fever (temperature > 38 degrees) at day 3.

11. Number of Subjects With the Presence of Fever. [Day 7]

    Number of subjects with the presence of fever (temperature > 38 degrees) at day 7.

12. Number of Subjects With the Presence of Fever. [Day 10]

    Number of subjects with the presence of fever (temperature > 38 degrees) at day 10.

13. Number of Subjects With the Presence of Fever. [Day 14]

    Number of subjects with the presence of fever (temperature > 38 degrees) at day 14.

14. Number of Subjects With the Presence of Shortness of Breath. [Day 3]

    Number of subjects with the presence of shortness of breath at day 3.

15. Number of Subjects With the Presence of Shortness of Breath. [Day 7]

    Number of subjects with the presence of shortness of breath at day 7.

16. Number of Subjects With the Presence of Shortness of Breath. [Day 10]

    Number of subjects with the presence of shortness of breath at day 10.

17. Number of Subjects With the Presence of Shortness of Breath. [Day 14]

    Number of subjects with the presence of shortness of breath at day 14.

18. Number of Subjects With the Presence of Anosmia. [Day 3]

    Number of subjects with the presence of anosmia at day 3.

19. Number of Subjects With the Presence of Anosmia. [Day 7]

    Number of subjects with the presence of anosmia at day 7.

20. Number of Subjects With the Presence of Anosmia. [Day 10]

    Number of subjects with the presence of anosmia at day 10.

21. Number of Subjects With the Presence of Anosmia. [Day 14]

    Number of subjects with the presence of anosmia at day 14.

22. Number of Subjects With the Presence of Feverish or Chills. [Day 3]

    Number of subjects with the presence of feverish or chills at day 3.

23. Number of Subjects With the Presence of Feverish or Chills. [Day 7]

    Number of subjects with the presence of feverish or chills at day 7.

24. Number of Subjects With the Presence of Feverish or Chills. [Day 10]

    Number of subjects with the presence of feverish or chills at day 10.

25. Number of Subjects With the Presence of Feverish or Chills. [Day 14]

    Number of subjects with the presence of feverish or chills at day 14.

26. Number of Subjects With the Presence of Sore Throat. [Day 3]

    Number of subjects with the presence of sore throat at day 3.

27. Number of Subjects With the Presence of Sore Throat. [Day 7]

    Number of subjects with the presence of sore throat at day 7.

28. Number of Subjects With the Presence of Sore Throat. [Day 10]

    Number of subjects with the presence of sore throat at day 10.

29. Number of Subjects With the Presence of Sore Throat. [Day 14]

    Number of subjects with the presence of sore throat at day 14.

30. Number of Subjects With the Presence of Runny Nose. [Day 3]

    Number of subjects with the presence of runny nose at day 3.

31. Number of Subjects With the Presence of Runny Nose. [Day 7]

    Number of subjects with the presence of runny nose at day 7.

32. Number of Subjects With the Presence of Runny Nose. [Day 10]

    Number of subjects with the presence of runny nose at day 10.

33. Number of Subjects With the Presence of Runny Nose. [Day 14]

    Number of subjects with the presence of runny nose at day 14.

34. Number of Subjects With the Presence of Nausea/Vomiting. [Day 3]

    Number of subjects with the presence of nausea/vomiting at day 3.

35. Number of Subjects With the Presence of Nausea/Vomiting. [Day 7]

    Number of subjects with the presence of nausea/vomiting at day 7.

36. Number of Subjects With the Presence of Nausea/Vomiting. [Day 10]

    Number of subjects with the presence of nausea/vomiting at day 10.

37. Number of Subjects With the Presence of Nausea/Vomiting. [Day 14]

    Number of subjects with the presence of nausea/vomiting at day 14.

38. Number of Subjects With the Presence of Headache. [Day 3]

    Number of subjects with the presence of headache at day 3.

39. Number of Subjects With the Presence of Headache. [Day 7]

    Number of subjects with the presence of headache at day 7.

40. Number of Subjects With the Presence of Headache. [Day 10]

    Number of subjects with the presence of headache at day 10.

41. Number of Subjects With the Presence of Headache. [Day 14]

    Number of subjects with the presence of headache at day 14.

42. Number of Subjects With the Presence of General Weakness. [Day 3]

    Number of subjects with the presence of general weakness at day 3.

43. Number of Subjects With the Presence of General Weakness. [Day 7]

    Number of subjects with the presence of general weakness at day 7.

44. Number of Subjects With the Presence of General Weakness. [Day 10]

    Number of subjects with the presence of general weakness at day 10.

45. Number of Subjects With the Presence of General Weakness. [Day 14]

    Number of subjects with the presence of general weakness at day 14.

46. Number of Subjects With the Presence of Pain. [Day 3]

    Number of subjects with the presence of pain at day 3.

47. Number of Subjects With the Presence of Pain. [Day 7]

    Number of subjects with the presence of pain at day 7.

48. Number of Subjects With the Presence of Pain. [Day 10]

    Number of subjects with the presence of pain at day 10.

49. Number of Subjects With the Presence of Pain. [Day 14]

    Number of subjects with the presence of pain at day 14.

50. Number of Subjects With the Presence of Irritability/Confusion. [Day 3]

    Number of subjects with the presence of irritability/confusion at day 3.

51. Number of Subjects With the Presence of Irritability/Confusion. [Day 7]

    Number of subjects with the presence of irritability/confusion at day 7.

52. Number of Subjects With the Presence of Irritability/Confusion. [Day 10]

    Number of subjects with the presence of irritability/confusion at day 10.

53. Number of Subjects With the Presence of Irritability/Confusion. [Day 14]

    Number of subjects with the presence of irritability/confusion at day 14.

54. Number of Subjects With the Presence of Diarrhea. [Day 3]

    Number of subjects with the presence of diarrhea at day 3.

55. Number of Subjects With the Presence of Diarrhea. [Day 7]

    Number of subjects with the presence of diarrhea at day 7.

56. Number of Subjects With the Presence of Diarrhea. [Day 10]

    Number of subjects with the presence of diarrhea at day 10.

57. Number of Subjects With the Presence of Diarrhea. [Day 14]

    Number of subjects with the presence of diarrhea at day 14.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Covid-19 positive by polymerase chain reaction (PCR) testing;

• Participant must be able to evaluate their symptoms and report them in the symptoms diary;

• Patients must be able to take their oral temperature daily with an electronic thermometer provided to them with study materials;

• Males and females, at least 18 years of age, capable and willing to provide informed consent;

• Female patient is either not of childbearing potential, defined as postmenopausal for at least 1 year or surgically sterile, or is of childbearing potential and practicing at least one method of contraception and preferably two complementary forms of contraception including a barrier method (e.g. male or female condoms, spermicides, sponges, foams, jellies, diaphragm, intrauterine device (IUD)) throughout the study;

• Patient must have received a diagnosis of COVID-19 infection within the last 48 hours and have one or more symptoms;

• Outpatient setting (not currently hospitalized or under immediate consideration for hospitalization);

• Patient must be able and willing to comply with the requirements of this study protocol.

Exclusion Criteria:

• Patient currently hospitalized or under immediate consideration for hospitalization;

• Patient currently in shock or with hemodynamic instability;

• Patient undergoing chemotherapy for cancer;

• Patient is unable to take oral temperature using an electronic thermometer;

• Patient who received at least one dose of the COVID-19 vaccine;

• Female patient who is pregnant or breast-feeding or is considering becoming pregnant during the study;

• People taking anticoagulant/antiplatelet medications, those with bleeding disorders, and people two weeks before or after surgery;

• Patient is considered by the investigator, for any reason, to be an unsuitable candidate for the study;

• Regular consumption of natural products containing more than 150 mg of hesperidin or regular consumption of more than 1 glass of orange juice per day;

• Known allergy to any of the medicinal and non-medicinal ingredient: hesperidin, microcrystalline cellulose, magnesium stearate.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Montreal Heart Institute	Montréal	Quebec	Canada	H1T1C8

Sponsors and Collaborators

• Montreal Heart Institute
• Ingenew Pharmaceuticals Inc.

Investigators

• Principal Investigator: Jocelyn Dupuis, MD, Montreal Heart Institute

Study Documents (Full-Text)

• Study Protocol - Feb 17, 2021
• Statistical Analysis Plan - Apr 29, 2021
• Informed Consent Form - Jan 21, 2021

More Information

Publications

None provided.

• Responsible Party: Montreal Heart Institute
• ClinicalTrials.gov Identifier: NCT04715932
• Other Study ID Numbers: MHICC-2020-003
• First Posted: Jan 20, 2021
• Last Update Posted: Apr 8, 2022
• Last Verified: Apr 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: COVID-19; Pharyngitis; Muscle Weakness; Arthralgia; Myalgia; Dyspnea; Confusion; Anosmia; Headache; Vomiting; Chest Pain; Abdominal Pain

Study Results

Participant Flow

Recruitment Details	216 subjects were randomized into the study with 109 assigned to placebo and 107 to hesperidin.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Period Title: Overall Study
STARTED	107	109
COMPLETED	106	109
NOT COMPLETED	1	0

Baseline Characteristics

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg	Total
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Total of all reporting groups
Overall Participants	107	109	216
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.31 (13.02)	40.67 (11.26)	40.98 (12.14)
Sex: Female, Male (Count of Participants)
Female	59 55.1%	60 55%	119 55.1%
Male	48 44.9%	49 45%	97 44.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 2.8%	4 3.7%	7 3.2%
Not Hispanic or Latino	104 97.2%	105 96.3%	209 96.8%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 0.9%	0 0%	1 0.5%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	3 2.8%	2 1.8%	5 2.3%
White	102 95.3%	107 98.2%	209 96.8%
More than one race	1 0.9%	0 0%	1 0.5%
Unknown or Not Reported	0 0%	0 0%	0 0%
Body Mass Index (BMI) (KG/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [KG/m^2]	28.12 (6.38)	28.21 (6.82)	28.16 (6.59)
Diabetes (Count of Participants)
With Diabetes	6 5.6%	1 0.9%	7 3.2%
Without Diabetes	101 94.4%	108 99.1%	209 96.8%
Hypertension (Count of Participants)
With Hypertension	14 13.1%	9 8.3%	23 10.6%
Without Hypertension	93 86.9%	100 91.7%	193 89.4%
Respiratory Disease (Count of Participants)
With Respiratory Disease	15 14%	18 16.5%	33 15.3%
Without Respiratory Disease	92 86%	91 83.5%	183 84.7%
Asthma (Count of Participants)
With Asthma	14 13.1%	17 15.6%	31 14.4%
Without Asthma	93 86.9%	92 84.4%	185 85.6%
Chronic Obstructive Pulmonary Disease (COPD) (Count of Participants)
With COPD	0 0%	1 0.9%	1 0.5%
Without COPD	107 100%	108 99.1%	215 99.5%
Pulmonary Fibrosis (Count of Participants)
With Pulmonary Fibrosis	1 0.9%	0 0%	1 0.5%
Without Pulmonary Fibrosis	106 99.1%	109 100%	215 99.5%
Other Respiratory Disease (Count of Participants)
With Other Respiratory Disease	0 0%	1 0.9%	1 0.5%
Without Other Respiratory Disease	107 100%	108 99.1%	215 99.5%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects With COVID-19 Symptoms at Day 3.
Description	Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
Subject has at least one of the selected COVID-19 symptoms.	93 86.9%	90 82.6%
Subject has none of the selected COVID-19 symptoms.	9 8.4%	13 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3849
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression).
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.49
	Confidence Interval	(2-Sided) 95%; 0.60 to 3.69
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Number of Subjects With COVID-19 Symptoms at Day 7.
Description	Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	101
Subject has at least one of the selected COVID-19 symptoms.	74 69.2%	76 69.7%
Subject has none of the selected COVID-19 symptoms.	17 15.9%	25 22.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3139
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.43
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Number of Subjects With COVID-19 Symptoms at Day 10.
Description	Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	99
Subject has at least one of the selected COVID-19 symptoms.	58 54.2%	60 55%
Subject has none of the selected COVID-19 symptoms.	32 29.9%	39 35.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5886
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.18
	Confidence Interval	(2-Sided) 95%; 0.65 to 2.14
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Number of Subjects With COVID-19 Symptoms at Day 14.
Description	Number of subjects with any of the following COVID-19 symptoms: fever (temperature > 38 degrees), cough, shortness of breath or anosmia, at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	94
Subject has at least one of the selected COVID-19 symptoms.	39 36.4%	55 50.5%
Subject has none of the selected COVID-19 symptoms.	40 37.4%	39 35.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2328
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 95%; 0.38 to 1.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Mean Number of COVID-19 Symptoms at Day 3.
Description	Mean number of COVID-19 symptoms (range 0-13) at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	101	102
Mean (Standard Deviation) [Symptoms]	4.74 (2.52)	4.16 (2.39)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1560
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated poisson regression).
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.95 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Mean Number of COVID-19 Symptoms at Day 7.
Description	Mean number of COVID-19 symptoms (range 0-13) at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	101
Mean (Standard Deviation) [Symptoms]	3.13 (2.49)	2.96 (2.46)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6233
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated poisson regression)
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.06
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.33
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Mean Number of COVID-19 Symptoms at Day 10.
Description	Mean number of COVID-19 symptoms (range 0-13) at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	99
Mean (Standard Deviation) [Symptoms]	2.01 (2.19)	1.95 (2.12)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8290
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated poisson regression)
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.78 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Mean Number of COVID-19 Symptoms at Day 14.
Description	Mean number of COVID-19 symptoms (range 0-13) at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	94
Mean (Standard Deviation) [Symptoms]	1.38 (1.76)	1.40 (1.65)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9222
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated poisson regression)
Method of Estimation	Estimation Parameter	Rate Ratio
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.69 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Number of Subjects With Complete Disappearance of Any Symptom.
Description	The descriptive statistics are the number of participants having complete disappearance of any symptom.
Time Frame	From randomization to occurence of first event, assessed up to 14 days

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	106	106
Complete disappearance of COVID-19 symptoms after randomization	29 27.1%	33 30.3%
No complete disappearance of COVID-19 symptoms after randomization	77 72%	73 67%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8834
	Comments
	Method	Log Rank
	Comments

10. Secondary Outcome

Title	Number of Subjects With the Cough Symptom.
Description	Number of subjects with the cough symptom at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With Cough Symptom	54 50.5%	54 49.5%
Without Cough Symptom	48 44.9%	49 45%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9416
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.02
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Number of Subjects With the Cough Symptom.
Description	Number of subjects with the cough symptom at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With Cough Symptom	37 34.6%	45 41.3%
Without Cough Symptom	54 50.5%	57 52.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6296
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.87
	Confidence Interval	(2-Sided) 95%; 0.49 to 1.55
	Parameter Dispersion	Type: Value:
	Estimation Comments

12. Secondary Outcome

Title	Number of Subjects With the Cough Symptom.
Description	Number of subjects with the cough symptom at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With Cough Symptom	26 24.3%	35 32.1%
Without Cough Symptom	64 59.8%	65 59.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3711
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.75
	Confidence Interval	(2-Sided) 95%; 0.41 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

13. Secondary Outcome

Title	Number of Subjects With the Cough Symptom.
Description	Number of subjects with the cough symptom at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With Cough Symptom	21 19.6%	29 26.6%
Without Cough Symptom	58 54.2%	66 60.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5696
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.42 to 1.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

14. Secondary Outcome

Title	Number of Subjects With the Presence of Fever.
Description	Number of subjects with the presence of fever (temperature > 38 degrees) at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	101	102
With the presence of fever	5 4.7%	6 5.5%
Without the presence of fever	96 89.7%	96 88.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7583
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.83
	Confidence Interval	(2-Sided) 95%; 0.26 to 2.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

15. Secondary Outcome

Title	Number of Subjects With the Presence of Fever.
Description	Number of subjects with the presence of fever (temperature > 38 degrees) at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	101
With the presence of fever	3 2.8%	4 3.7%
Without the presence of fever	87 81.3%	97 89%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8091
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.84
	Confidence Interval	(2-Sided) 95%; 0.20 to 3.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

16. Secondary Outcome

Title	Number of Subjects With the Presence of Fever.
Description	Number of subjects with the presence of fever (temperature > 38 degrees) at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	99
With the Presence of Fever	3 2.8%	2 1.8%
Without the Presence of Fever	87 81.3%	97 89%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5591
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.67
	Confidence Interval	(2-Sided) 95%; 0.30 to 9.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

17. Secondary Outcome

Title	Number of Subjects With the Presence of Fever.
Description	Number of subjects with the presence of fever (temperature > 38 degrees) at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	94
With the presence of fever	0 0%	1 0.9%
Without the presence of fever	79 73.8%	93 85.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9983
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)

18. Secondary Outcome

Title	Number of Subjects With the Presence of Shortness of Breath.
Description	Number of subjects with the presence of shortness of breath at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of shortness of breath	46 43%	35 32.1%
Without the presence of shortness of breath	56 52.3%	68 62.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1068
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.60
	Confidence Interval	(2-Sided) 95%; 0.90 to 2.82
	Parameter Dispersion	Type: Value:
	Estimation Comments

19. Secondary Outcome

Title	Number of Subjects With the Presence of Shortness of Breath.
Description	Number of subjects with the presence of shortness of breath at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of shortness of breath	28 26.2%	30 27.5%
Without the presence of shortness of breath	63 58.9%	72 66.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8382
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.98
	Parameter Dispersion	Type: Value:
	Estimation Comments

20. Secondary Outcome

Title	Number of Subjects With the Presence of Shortness of Breath.
Description	Number of subjects with the presence of shortness of breath at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of shortness of breath	19 17.8%	18 16.5%
Without the presence of shortness of breath	71 66.4%	82 75.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5912
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.59 to 2.51
	Parameter Dispersion	Type: Value:
	Estimation Comments

21. Secondary Outcome

Title	Number of Subjects With the Presence of Shortness of Breath.
Description	Number of subjects with the presence of shortness of breath at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of shortness of breath	14 13.1%	13 11.9%
Without the presence of shortness of breath	65 60.7%	82 75.2%

22. Secondary Outcome

Title	Number of Subjects With the Presence of Anosmia.
Description	Number of subjects with the presence of anosmia at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of anosmia	52 48.6%	59 54.1%
Without the presence of anosmia	50 46.7%	44 40.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3686
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.45 to 1.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

23. Secondary Outcome

Title	Number of Subjects With the Presence of Anosmia.
Description	Number of subjects with the presence of anosmia at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of anosmia	43 40.2%	47 43.1%
Without the presence of anosmia	48 44.9%	55 50.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8711
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.05
	Confidence Interval	(2-Sided) 95%; 0.59 to 1.86
	Parameter Dispersion	Type: Value:
	Estimation Comments

24. Secondary Outcome

Title	Number of Subjects With the Presence of Anosmia.
Description	Number of subjects with the presence of anosmia at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of anosmia	34 31.8%	37 33.9%
Without the presence of anosmia	56 52.3%	63 57.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9124
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.03
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.87
	Parameter Dispersion	Type: Value:
	Estimation Comments

25. Secondary Outcome

Title	Number of Subjects With the Presence of Anosmia.
Description	Number of subjects with the presence of anosmia at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of anosmia	20 18.7%	31 28.4%
Without the presence of anosmia	59 55.1%	64 58.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2952
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.70
	Confidence Interval	(2-Sided) 95%; 0.36 to 1.37
	Parameter Dispersion	Type: Value:
	Estimation Comments

26. Secondary Outcome

Title	Number of Subjects With the Presence of Feverish or Chills.
Description	Number of subjects with the presence of feverish or chills at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of feverish or chills	24 22.4%	21 19.3%
Without the presence of feverish or chills	78 72.9%	82 75.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5894
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.20
	Confidence Interval	(2-Sided) 95%; 0.62 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

27. Secondary Outcome

Title	Number of Subjects With the Presence of Feverish or Chills.
Description	Number of subjects with the presence of feverish or chills at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of feverish or chills	10 9.3%	10 9.2%
Without the presence of feverish or chills	81 75.7%	92 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7887
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.14
	Confidence Interval	(2-Sided) 95%; 0.45 to 2.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

28. Secondary Outcome

Title	Number of Subjects With the Presence of Feverish or Chills.
Description	Number of subjects with the presence of feverish or chills at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of feverish or chills	4 3.7%	6 5.5%
Without the presence of feverish or chills	86 80.4%	94 86.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6348
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.20 to 2.70
	Parameter Dispersion	Type: Value:
	Estimation Comments

29. Secondary Outcome

Title	Number of Subjects With the Presence of Feverish or Chills.
Description	Number of subjects with the presence of feverish or chills at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of feverish or chills	1 0.9%	3 2.8%
Without the presence of feverish or chills	78 72.9%	92 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4257
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.39
	Confidence Interval	(2-Sided) 95%; 0.04 to 3.92
	Parameter Dispersion	Type: Value:
	Estimation Comments

30. Secondary Outcome

Title	Number of Subjects With the Presence of Sore Throat.
Description	Number of subjects with the presence of sore throat at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of sore throat	33 30.8%	23 21.1%
Without the presence of sore throat	69 64.5%	80 73.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1113
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.66
	Confidence Interval	(2-Sided) 95%; 0.89 to 3.11
	Parameter Dispersion	Type: Value:
	Estimation Comments

31. Secondary Outcome

Title	Number of Subjects With the Presence of Sore Throat.
Description	Number of subjects with the presence of sore throat at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of sore throat	17 15.9%	13 11.9%
Without the presence of sore throat	74 69.2%	89 81.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2613
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.57
	Confidence Interval	(2-Sided) 95%; 0.71 to 3.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

32. Secondary Outcome

Title	Number of Subjects With the Presence of Sore Throat.
Description	Number of subjects with the presence of sore throat at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of sore throat	6 5.6%	8 7.3%
Without the presence of sore throat	84 78.5%	92 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7273
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.27 to 2.49
	Parameter Dispersion	Type: Value:
	Estimation Comments

33. Secondary Outcome

Title	Number of Subjects With the Presence of Sore Throat.
Description	Number of subjects with the presence of sore throat at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of sore throat	3 2.8%	4 3.7%
Without the presence of sore throat	76 71%	91 83.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8909
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.90
	Confidence Interval	(2-Sided) 95%; 0.19 to 4.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

34. Secondary Outcome

Title	Number of Subjects With the Presence of Runny Nose.
Description	Number of subjects with the presence of runny nose at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of runny nose	48 44.9%	38 34.9%
Without the presence of runny nose	54 50.5%	65 59.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1438
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.87 to 2.67
	Parameter Dispersion	Type: Value:
	Estimation Comments

35. Secondary Outcome

Title	Number of Subjects With the Presence of Runny Nose.
Description	Number of subjects with the presence of runny nose at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of runny nose	25 23.4%	22 20.2%
Without the presence of runny nose	66 61.7%	80 73.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3440
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.71 to 2.68
	Parameter Dispersion	Type: Value:
	Estimation Comments

36. Secondary Outcome

Title	Number of Subjects With the Presence of Runny Nose.
Description	Number of subjects with the presence of runny nose at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of runny nose	18 16.8%	17 15.6%
Without the presence of runny nose	72 67.3%	83 76.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5968
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.22
	Confidence Interval	(2-Sided) 95%; 0.58 to 2.56
	Parameter Dispersion	Type: Value:
	Estimation Comments

37. Secondary Outcome

Title	Number of Subjects With the Presence of Runny Nose.
Description	Number of subjects with the presence of runny nose at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of runny nose	12 11.2%	10 9.2%
Without the presence of runny nose	67 62.6%	85 78%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.3620
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.52
	Confidence Interval	(2-Sided) 95%; 0.62 to 3.76
	Parameter Dispersion	Type: Value:
	Estimation Comments

38. Secondary Outcome

Title	Number of Subjects With the Presence of Nausea/Vomiting.
Description	Number of subjects with the presence of nausea/vomiting at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of nausea/vomiting	21 19.6%	12 11%
Without the presence of nausea/vomiting	81 75.7%	91 83.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0875
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.97
	Confidence Interval	(2-Sided) 95%; 0.91 to 4.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

39. Secondary Outcome

Title	Number of Subjects With the Presence of Nausea/Vomiting.
Description	Number of subjects with the presence of nausea/vomiting at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of nausea/vomiting	9 8.4%	11 10.1%
Without the presence of nausea/vomiting	82 76.6%	91 83.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8397
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 95%; 0.36 to 2.32
	Parameter Dispersion	Type: Value:
	Estimation Comments

40. Secondary Outcome

Title	Number of Subjects With the Presence of Nausea/Vomiting.
Description	Number of subjects with the presence of nausea/vomiting at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of nausea/vomiting	6 5.6%	5 4.6%
Without the presence of nausea/vomiting	84 78.5%	95 87.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6265
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95%; 0.40 to 4.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

41. Secondary Outcome

Title	Number of Subjects With the Presence of Nausea/Vomiting.
Description	Number of subjects with the presence of nausea/vomiting at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of nausea/vomiting	2 1.9%	2 1.8%
Without the presence of nausea/vomiting	77 72%	93 85.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8528
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.16 to 8.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

42. Secondary Outcome

Title	Number of Subjects With the Presence of Headache.
Description	Number of subjects with the presence of headache at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of headache	48 44.9%	41 37.6%
Without the presence of headache	54 50.5%	62 56.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2983
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.34
	Confidence Interval	(2-Sided) 95%; 0.77 to 2.35
	Parameter Dispersion	Type: Value:
	Estimation Comments

43. Secondary Outcome

Title	Number of Subjects With the Presence of Headache.
Description	Number of subjects with the presence of headache at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of headache	34 31.8%	34 31.2%
Without the presence of headache	57 53.3%	68 62.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5611
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.19
	Confidence Interval	(2-Sided) 95%; 0.66 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

44. Secondary Outcome

Title	Number of Subjects With the Presence of Headache.
Description	Number of subjects with the presence of headache at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of headache	22 20.6%	20 18.3%
Without the presence of headache	68 63.6%	80 73.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4643
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.29
	Confidence Interval	(2-Sided) 95%; 0.65 to 2.58
	Parameter Dispersion	Type: Value:
	Estimation Comments

45. Secondary Outcome

Title	Number of Subjects With the Presence of Headache.
Description	Number of subjects with the presence of headache at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of headache	10 9.3%	9 8.3%
Without the presence of headache	69 64.5%	86 78.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5063
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.38
	Confidence Interval	(2-Sided) 95%; 0.53 to 3.62
	Parameter Dispersion	Type: Value:
	Estimation Comments

46. Secondary Outcome

Title	Number of Subjects With the Presence of General Weakness.
Description	Number of subjects with the presence of general weakness at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of general weakness	63 58.9%	55 50.5%
Without the presence of general weakness	39 36.4%	48 44%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2292
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.41
	Confidence Interval	(2-Sided) 95%; 0.80 to 2.47
	Parameter Dispersion	Type: Value:
	Estimation Comments

47. Secondary Outcome

Title	Number of Subjects With the Presence of General Weakness.
Description	Number of subjects with the presence of general weakness at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of general weakness	39 36.4%	40 36.7%
Without the presence of general weakness	52 48.6%	62 56.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6097
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.16
	Confidence Interval	(2-Sided) 95%; 0.65 to 2.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

48. Secondary Outcome

Title	Number of Subjects With the Presence of General Weakness.
Description	Number of subjects with the presence of general weakness at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of general weakness	20 18.7%	21 19.3%
Without the presence of general weakness	70 65.4%	79 72.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8389
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.07
	Confidence Interval	(2-Sided) 95%; 0.54 to 2.16
	Parameter Dispersion	Type: Value:
	Estimation Comments

49. Secondary Outcome

Title	Number of Subjects With the Presence of General Weakness.
Description	Number of subjects with the presence of general weakness at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of general weakness	14 13.1%	17 15.6%
Without the presence of general weakness	65 60.7%	78 71.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9764
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.45 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments

50. Secondary Outcome

Title	Number of Subjects With the Presence of Pain.
Description	Number of subjects with the presence of pain at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of pain	44 41.1%	50 45.9%
Without the presence of pain	58 54.2%	53 48.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4403
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.46 to 1.40
	Parameter Dispersion	Type: Value:
	Estimation Comments

51. Secondary Outcome

Title	Number of Subjects With the Presence of Pain.
Description	Number of subjects with the presence of pain at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of pain	17 15.9%	23 21.1%
Without the presence of pain	74 69.2%	79 72.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.5112
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.39 to 1.60
	Parameter Dispersion	Type: Value:
	Estimation Comments

52. Secondary Outcome

Title	Number of Subjects With the Presence of Pain.
Description	Number of subjects with the presence of pain at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of pain	13 12.1%	14 12.8%
Without the presence of pain	77 72%	86 78.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.9306
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.04
	Confidence Interval	(2-Sided) 95%; 0.46 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

53. Secondary Outcome

Title	Number of Subjects With the Presence of Pain.
Description	Number of subjects with the presence of pain at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of pain	5 4.7%	8 7.3%
Without the presence of pain	74 69.2%	87 79.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6046
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.23 to 2.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

54. Secondary Outcome

Title	Number of Subjects With the Presence of Irritability/Confusion.
Description	Number of subjects with the presence of irritability/confusion at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of irritability/confusion	20 18.7%	18 16.5%
Without the presence of irritability/confusion	82 76.6%	85 78%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.6963
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 95%; 0.57 to 2.34
	Parameter Dispersion	Type: Value:
	Estimation Comments

55. Secondary Outcome

Title	Number of Subjects With the Presence of Irritability/Confusion.
Description	Number of subjects with the presence of irritability/confusion at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of irritability/confusion	6 5.6%	10 9.2%
Without the presence of irritability/confusion	85 79.4%	92 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.4250
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	0.65
	Confidence Interval	(2-Sided) 95%; 0.22 to 1.88
	Parameter Dispersion	Type: Value:
	Estimation Comments

56. Secondary Outcome

Title	Number of Subjects With the Presence of Irritability/Confusion.
Description	Number of subjects with the presence of irritability/confusion at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of irritability/confusion	4 3.7%	4 3.7%
Without the presence of irritability/confusion	86 80.4%	96 88.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8797
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.27 to 4.65
	Parameter Dispersion	Type: Value:
	Estimation Comments

57. Secondary Outcome

Title	Number of Subjects With the Presence of Irritability/Confusion.
Description	Number of subjects with the presence of irritability/confusion at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of irritability/confusion	3 2.8%	1 0.9%
Without the presence of irritability/confusion	76 71%	94 86.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2634
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	3.71
	Confidence Interval	(2-Sided) 95%; 0.37 to 37.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

58. Secondary Outcome

Title	Number of Subjects With the Presence of Diarrhea.
Description	Number of subjects with the presence of diarrhea at day 3.
Time Frame	Day 3

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	102	103
With the presence of diarrhea	22 20.6%	16 14.7%
Without the presence of diarrhea	80 74.8%	87 79.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.2710
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.50
	Confidence Interval	(2-Sided) 95%; 0.73 to 3.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

59. Secondary Outcome

Title	Number of Subjects With the Presence of Diarrhea.
Description	Number of subjects with the presence of diarrhea at day 7.
Time Frame	Day 7

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	91	102
With the presence of diarrhea	15 14%	10 9.2%
Without the presence of diarrhea	76 71%	92 84.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.1748
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.82
	Confidence Interval	(2-Sided) 95%; 0.77 to 4.30
	Parameter Dispersion	Type: Value:
	Estimation Comments

60. Secondary Outcome

Title	Number of Subjects With the Presence of Diarrhea.
Description	Number of subjects with the presence of diarrhea at day 10.
Time Frame	Day 10

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	90	100
With the presence of diarrhea	6 5.6%	6 5.5%
Without the presence of diarrhea	84 78.5%	94 86.2%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.8513
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.12
	Confidence Interval	(2-Sided) 95%; 0.34 to 3.63
	Parameter Dispersion	Type: Value:
	Estimation Comments

61. Secondary Outcome

Title	Number of Subjects With the Presence of Diarrhea.
Description	Number of subjects with the presence of diarrhea at day 14.
Time Frame	Day 14

Outcome Measure Data

Analysis Population Description

Number of patients analysed differs from the number of patients assigned to the arm or comparison group as not all subjects replied to the questionnaire or follow-up call, whether a symptom occurred or not.

Arm/Group Title	Hesperidin 1000mg	Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.	Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
Measure Participants	79	95
With the presence of diarrhea	4 3.7%	4 3.7%
Without the presence of diarrhea	75 70.1%	91 83.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Hesperidin 1000mg, Placebo 1000mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.7906
	Comments
	Method	Mixed Models Analysis
	Comments	Generalized linear mixed model (repeated binary logistic regression)
Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.21
	Confidence Interval	(2-Sided) 95%; 0.29 to 5.07
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Adverse event data were collected between randomization/baseline until the end of study visit (up to 14 days).
Adverse Event Reporting Description	Subjects reporting multiple TEAEs within a given system organ class/preferred term were counted only once within the category. Results are based on safety population. Table of adverse events includes serious adverse events. Number of Participants at Risk differs from the number of participants assigned to the arm or comparison group. One participant from the placebo group is not part of the safety population. However, "All-Cause Mortality" is on the intention to treat population.
Arm/Group Title	Hesperidin 1000mg		Placebo 1000mg
Arm/Group Description	Patients will receive study medication Hesperidin and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.		Patients will receive study medication Placebo and will take 2 capsules of 500mg at the same time in the evening, at bedtime with water.
All Cause Mortality
	Hesperidin 1000mg		Placebo 1000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/107 (0%)		0/109 (0%)
Serious Adverse Events
	Hesperidin 1000mg		Placebo 1000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/107 (3.7%)		1/108 (0.9%)
Infections and infestations
Arthritis bacterial	3/107 (2.8%)		1/108 (0.9%)
Pneumonia	2/107 (1.9%)		1/108 (0.9%)
Metabolism and nutrition disorders
Dehydration	1/107 (0.9%)		0/108 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory distress	1/107 (0.9%)		0/108 (0%)
Other (Not Including Serious) Adverse Events
	Hesperidin 1000mg		Placebo 1000mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	20/107 (18.7%)		16/108 (14.8%)
Gastrointestinal disorders
Abdominal pain	2/107 (1.9%)		0/108 (0%)
Cheilitis	1/107 (0.9%)		0/108 (0%)
Diarrhoea	0/107 (0%)		2/108 (1.9%)
Gastrointestinal disorder	2/107 (1.9%)		0/108 (0%)
Vomiting	1/107 (0.9%)		0/108 (0%)
Infections and infestations
Arthritis bacterial	1/107 (0.9%)		0/108 (0%)
Lower respiratory tract infection	6/107 (5.6%)		4/108 (3.7%)
Pneumonia	4/107 (3.7%)		3/108 (2.8%)
Sinusitis	1/107 (0.9%)		4/108 (3.7%)
Metabolism and nutrition disorders
Dehydration	1/107 (0.9%)		0/108 (0%)
Nervous system disorders
Hypoaesthesia	1/107 (0.9%)		0/108 (0%)
Loss of consciousness	0/107 (0%)		1/108 (0.9%)
Respiratory, thoracic and mediastinal disorders
Increased bronchial secretion	1/107 (0.9%)		0/108 (0%)
Respiratory distress	1/107 (0.9%)		0/108 (0%)
Skin and subcutaneous tissue disorders
Rash	1/107 (0.9%)		2/108 (1.9%)

Limitations/Caveats

Only one dosage regimen of hesperidin was tested in this trial.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.