A Study of the Efficacy and Safety of Ranquilon Tablets in Patients With Anxiety in Neurasthenia and Adjustment Disorders

Anxiety Clinical Trial

Official title:

A Double-blind, Randomized, Placebo-controlled, Multicenter Phase III Clinical Trial to Examine the Clinical Efficacy and Safety of Ranquilon, 1 mg Tablets in Patients With Anxiety in Neurasthenia and Adjustment Disorders

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT05586789
• Other study ID #: RAN-03-03-2022
• Status: Completed
• Phase: Phase 3
• Start date: October 12, 2022
• Est. completion date: January 3, 2023

Study information

• Verified date: July 2023
• Source: Valenta Pharm JSC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of the study is to evaluate the efficacy of Ranquilon, 1 mg tablets, at a dose of 6 mg/day compared to placebo for the treatment of patients with anxiety in neurasthenia and adjustment disorder. An additional study objective was to evaluate the safety of Ranquilon, 1 mg tablets, at a dose of 6 mg/day compared to placebo in patients with anxiety in neurasthenia and adjustment disorder.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 220
• Est. completion date: January 3, 2023
• Est. primary completion date: November 22, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

Inclusion Criteria:

1. Men and women between the ages of 18 and 70

2. Presence of written consent to participate in the study in accordance with applicable law

3. Patients with anxiety and diagnoses based on ICD-10 criteria: neurasthenia (F48.0) or adjustment disorder (F43.2)

4. HARS anxiety scores of 18-24

5. Severity of asthenia on the Asthenia Self Assessment Scale (MFI-20) of more than 50 points

6. Hamilton Depression Assessment Scale (HAMD-17) score < 6

7. CGI-s scale score of at least 4

8. Negative pregnancy test for women of preserved reproductive potential

9. Consent to use effective contraception for the duration of the study and 30 days after completion (for women of unresolved reproductive potential and men)

10. Ability to understand the requirements for study participants, to give written consent to participate in the study (including the use and communication of patient health information relevant to the study) and to comply with the procedures of the study protocol

Exclusion Criteria:

1. Known intolerance to the active ingredient and/or excipients in the study drug/placebo of the study drug

2. Known presence of lactase deficiency, lactose intolerance, glucose-galactose malabsorption or galactose intolerance

3. Patients who require concomitant therapy prohibited in this study (MAO inhibitors, antidepressants, neuroleptics, anxiolytics and sedatives (including herbal), sleeping pills when used on a continuous basis), or have taken these drugs within the last month

4. Established or suspected alcohol/drug use at the time of screening or randomization, and/or a history of alcohol, drug or drug dependence

5. Presence of cancer, including a history of cancer (with the exception of a cured tumor with sustained remission for more than 5 years)

6. Presence of tuberculosis, including a history of tuberculosis

7. The presence of HIV, chronic viral hepatitis B/C, syphilis (including a history), or a positive test for HIV, hepatitis B/C, syphilis at screening

8. Patients with a diagnosis established on the basis of ICD-10 criteria: other anxiety disorders (F41)

9. Schizophrenia, schizoaffective, affective and panic disorders

10. Acute psychosis (endogenous-procedural, organic or somatogenic), including history

11. Organic lesions of the central nervous system of traumatic and alcoholic genesis

12. Postencephalitic syndrome

13. Brain tumors, including in the anamnesis

14. Degenerative diseases of the central nervous system (CNS), in particular, multiple sclerosis

15. Depression, including a history of depression

16. Generalized anxiety disorder, including a history

17. Suicidal thoughts or ideas; a history of suicide attempts

18. Epilepsy, seizures, including a history of seizures

19. Diabetes mellitus at the stage of decompensation

20. Established diagnosis of chronic kidney disease stage 3A or higher, or glomerular filtration rate (GFR) calculated by the Cockcroft-Gault formula = 59 ml/min/1.73 m2 or less

21. Established diagnosis of hepatic failure of any severity, or elevated ALT, AST or total bilirubin, urea >3 times the upper limit of normal values

22. Conditions after major surgical interventions, if less than six months have elapsed since the intervention

23. Chronic heart failure New York Heart Association (NYHA) functional class III-IV

24. Severe, decompensated, or unstable disease (any disease or condition that threatens the patient's life or worsens the patient's prognosis, or makes it impossible to perform a clinical trial in the patient)

25. Pregnant women, women breastfeeding, or women planning to become pregnant during the study and 30 days after study participation ends

26. Refusal by the patient to use approved contraception or to completely abstain from sexual intercourse during the entire period of study participation, beginning at Visit 0, and for 30 days after completion of study participation

27. Patient's current or planned participation in psychological or psychotherapeutic interventions designed to treat an anxiety disorder during the course of the clinical trial

28. Participation in any other clinical trial within 90 days prior to the screening period

29. Lack of willingness to cooperate on the part of the patient

30. Other reasons that, in the opinion of the investigator, prevent the patient from participating in the study or pose an unreasonable risk to the patient

Withdrawal Criteria:

1. Patient's desire to stop participating in the study (withdrawal of informed consent) Each patient has the right to stop participating in the study at any time without giving a reason. Withdrawal from the study will not affect the medical care provided to the patient in the future.

2. A decision by the research physician that the patient should be excluded is in the patient's own best interest

3. Patient refuses to cooperate with the investigator or is undisciplined

4. Causes/occurrence of situations during the study that threaten patient safety (e.g., hypersensitivity reactions, SAE, etc.)

5. Inclusion of a patient in the study with inclusion/inclusion criteria not met (prior to randomization)

6. Significant violation of the treatment regimen A significant violation is defined as a) skipping study drug/placebo for 2 consecutive full days or more, or b) taking, in total, < 80% or >120% of the full course (full course = 168 pills)

7. Positive pregnancy test

8. Confirmed diagnosis of COVID-19

9. Occurrence in the course of the study of other reasons that prevent the study according to the protocol

10. Death of a patient

Related Conditions & MeSH terms

• Adjustment Disorders
• Anxiety
• Anxiety Disorders
• Neurasthenia

Intervention

Drug:
• Ranquilon
Two 1 mg tablets 3 times per day for 28 days
• Placebo
Two tablets 3 times per day for 28 days

Locations

Country	Name	City	State
Russian Federation	Engels Psychiatric Hospital State Health Care Institution of the Ministry of Health of the Saratov Region	Engels
Russian Federation	State Budgetary Health Institution of Nizhny Novgorod Oblast "Clinical Psychiatric Hospital No. 1 of Nizhny Novgorod. Nizhny Novgorod"	Nizhny Novgorod
Russian Federation	Professors' Clinic LLC.	Perm
Russian Federation	EosMED JSC	Saint Petersburg
Russian Federation	Limited Liability Company "Energy of Health"	Saint Petersburg
Russian Federation	Limited Liability Company "Meili"	Saint Petersburg
Russian Federation	Limited Liability Company "Research Center Eco-Safety"	Saint Petersburg
Russian Federation	Limited Liability Company "Research Center Eco-Security"	Saint Petersburg
Russian Federation	LLC "Aurora MedFort"	Saint Petersburg
Russian Federation	Saratov City Psychoneurological Dispensary	Saratov

Sponsors (1)

Lead Sponsor	Collaborator
Valenta Pharm JSC

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in patient status on the Hamilton Anxiety Rating Scale (HARS): Percentage of patients with a significant, i.e., 50% or greater reduction from baseline, in HARS anxiety levels on Day 29 ± 1	HARS scale includes 14 items, each of which is rated on the Likken scale. Of these, 13 items relate to the manifestation of anxiety in daily life, 14 items relate to the manifestation of anxiety during examinations. The sum of the scores may range from 0 to 56, with scores 0 to 7 corresponding to the absence of anxiety, 8 to 17 to the presence of symptoms of anxiety disorder, 18 to 24 to moderate severity of anxiety disorder, and 25 to 56 to severe severity of anxiety disorder.	Day 29 ± 1 of the study
Secondary	Proportion of patients with a significant, i.e., 50% or greater reduction in HARS anxiety level on Day 15 ± 1 (Visit 2)	HARS scale includes 14 items, each of which is rated on the Likken scale. Of these, 13 items relate to the manifestation of anxiety in daily life, 14 items relate to the manifestation of anxiety during examinations. The sum of the scores may range from 0 to 56, with scores 0 to 7 corresponding to the absence of anxiety, 8 to 17 to the presence of symptoms of anxiety disorder, 18 to 24 to moderate severity of anxiety disorder, and 25 to 56 to severe severity of anxiety disorder.	Day 15 ± 1 of the study
Secondary	Change in HARS anxiety level on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3) compared to baseline	HARS scale includes 14 items, each of which is rated on the Likken scale. Of these, 13 items relate to the manifestation of anxiety in daily life, 14 items relate to the manifestation of anxiety during examinations. The sum of the scores may range from 0 to 56, with scores 0 to 7 corresponding to the absence of anxiety, 8 to 17 to the presence of symptoms of anxiety disorder, 18 to 24 to moderate severity of anxiety disorder, and 25 to 56 to severe severity of anxiety disorder.	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Proportion of patients with HARS anxiety scores reduced to 17 or less on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3)	HARS scale includes 14 items, each of which is rated on the Likken scale. Of these, 13 items relate to the manifestation of anxiety in daily life, 14 items relate to the manifestation of anxiety during examinations. The sum of the scores may range from 0 to 56, with scores 0 to 7 corresponding to the absence of anxiety, 8 to 17 to the presence of symptoms of anxiety disorder, 18 to 24 to moderate severity of anxiety disorder, and 25 to 56 to severe severity of anxiety disorder.	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Time to decrease the HARS anxiety level to a score of 17 or less	HARS scale includes 14 items, each of which is rated on the Likken scale. Of these, 13 items relate to the manifestation of anxiety in daily life, 14 items relate to the manifestation of anxiety during examinations. The sum of the scores may range from 0 to 56, with scores 0 to 7 corresponding to the absence of anxiety, 8 to 17 to the presence of symptoms of anxiety disorder, 18 to 24 to moderate severity of anxiety disorder, and 25 to 56 to severe severity of anxiety disorder.	Screening, Day 15 ± 1, Day 29 ± 1 of the study, the end of the study (Day 44 ± 1) or an early termination visit, whichever came first
Secondary	Proportion of patients with significant and marked improvement as assessed by the physician (Clinical Global Impression - improvement (CGI-i) score 1 or 2) at Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3)	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Proportion of patients with a CGI-s score of 1 or 2 as assessed by the physician (healthy or borderline disorder) on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3)	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Time to significant or marked improvement - achieving a score of 1 or 2 on the CGI-i scale	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Screening, Day 15 ± 1, Day 29 ± 1 of the study, or an early termination visit, whichever came first
Secondary	Time to decrease in severity of condition to 2 points or to 1 point or CGI-s scale	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Screening, Day 15 ± 1, Day 29 ± 1 of the study, the end of the study (Day 44 ± 1) or an early termination visit, whichever came first
Secondary	Absolute value of the patient's CGI-i score by Days 15 ± 1 (Visit 2) and 29 ± 1 (Visit 3)	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Change in patient severity on the CGI-s scale by Days 15 ± 1 (Visit 2) and 29 ± 1 (Visit 3) compared to baseline	The Clinical Global Impression Scale (CGI) includes two subscales: one for severity of symptoms and one for progression of symptoms with treatment. The first subscale is called Clinical Global Impression - severity (CGI-s) and the second subscale is Clinical Global Impression - improvement (CGI-i). CGI-s includes scores from 0 (healthy) to 7 (very severe); CGI-i includes scores from 1 (marked improvement) to 7 (marked deterioration)	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Change in the Multidimensional Fatigue Fatigue Inventory (MFI-20) total score on Day 15 ± 1 (Visit 2) and 29 ± 1 (Visit 3) compared to baseline	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Day 15 ± 1 and Day 29 ± 1 of the study
Secondary	Time to decrease the MFI-20 cumulative score to 30 points or less	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Screening, Day 15 ± 1, Day 29 ± 1 of the study, or an early termination visit, whichever came first
Secondary	Time to decrease the MFI-20 cumulative score by 25% and 50% from baseline	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Screening, Day 15 ± 1, Day 29 ± 1 of the study, or an early termination visit, whichever came first
Secondary	Proportion of patients with a 25% reduction in MFI-20 total score on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3) from baseline	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Day 15 ± 1 and Day 29 ± 1
Secondary	Proportion of patients with a 50% reduction in MFI-20 total score on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3) from baseline	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Day 15 ± 1 and Day 29 ± 1
Secondary	Proportion of patients with a decrease in their MFI-20 cumulative score to 30 on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3)	The Multidimensional Fatigue Fatigue Inventory (MFI-20) provides a subjective quantitative assessment of the overall severity of asthenia and its various aspects. This scale consists of 20 items reflecting the main components of asthenic syndrome, such as: general asthenia, physical asthenia, mental asthenia, decreased activity and decreased motivation. The patient was given an opportunity to rate the mentioned items to his/her condition on a five-point scale. The score of the scale is the sum of the points of its individual constituent items and can vary in the range from 5 to 25 points. Normally, the total number of points should not exceed 30. If the total score on one of the subscales was higher than 12, this could be a preliminary ground for classifying the condition as an asthenic syndrome	Day 15 ± 1 and Day 29 ± 1
Secondary	Change in Spielberger personality anxiety level on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3) compared to baseline	The Spielberger Questionnaire includes a series of statements describing personal and situational anxiety, the answers to which are scored from 1 (least severe or prolonged) to 4 (most severe or prolonged). The patient reads the statements and independently chooses the most appropriate frequency for each statement. When analyzing the results of the self-assessment, you should keep in mind that the overall total for each of the subscales may range from 20 to 80 points. The higher the total score, the higher the level of anxiety (situational or personal).	Day 15 ± 1 and Day 29 ± 1
Secondary	Change in situational anxiety levels on the Spielberger questionnaire on Day 15 ± 1 (Visit 2) and Day 29 ± 1 (Visit 3) compared to baseline	The Spielberger Questionnaire includes a series of statements describing personal and situational anxiety, the answers to which are scored from 1 (least severe or prolonged) to 4 (most severe or prolonged). The patient reads the statements and independently chooses the most appropriate frequency for each statement. When analyzing the results of the self-assessment, you should keep in mind that the overall total for each of the subscales may range from 20 to 80 points. The higher the total score, the higher the level of anxiety (situational or personal).	Day 15 ± 1 and Day 29 ± 1
Secondary	Safety and Tolerability: adverse event (AE) rate	Number and frequency of adverse events (AEs) or serious AEs (SAEs)	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 44 ± 1 for each participant
Secondary	Safety and Tolerability: AEs associated with the study drug	Number and frequency of AEs or SAEs associated with the study drug	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 44 ± 1 for each participant
Secondary	Safety and Tolerability: treatment discontinuation	Percentage of patients who discontinued treatment due to the occurrence of AEs/SAEs	From the date of screening (and signing informed consent form) to the end of the study or to an early termination visit, whichever came first, assessed up to day 44 ± 1 for each participant
Secondary	Safety and Tolerability: vital signs - systolic blood pressure (SBP)	SBP, mmHg	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: vital signs - diastolic blood pressure (DBP)	DBP, mmHg	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: vital signs - respiratory rate (RR)	RR, breaths per minute	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: vital signs - heart rate (HR)	HR, beats per minute	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: vital signs - body temperature	Body temperature, centigrade scale	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: physical examination results	Physical examination will follow the general rules of internal medicine: general examination, examination of mucous membranes and skin, including palpation of lymph nodes, evaluation of the musculoskeletal system, palpation, percussion, and auscultation of the main organ systems (cardiovascular, respiratory, digestive, and urinary systems) will be performed sequentially	Screening, day 1, day 15, day 29, and day 44 of the study or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: 12-lead electrocardiogram (ECG) - heart rate	12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: heart rate (beats per minute)	Screening, day 29, or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: 12-lead electrocardiogram (ECG) - PQ interval	12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: PQ interval (ms)	Screening, day 29, or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: 12-lead electrocardiogram (ECG) - QRS complex	12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QRS complex (ms)	Screening, day 29, or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: 12-lead electrocardiogram (ECG) - corrected QT interval (QTc)	12-lead ECG (I, II, III, aVR, aVL, aVF, V1-V6) taken while lying down: QTc (ms)	Screening, day 29, or on the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - hemoglobin	Hemoglobin, g/dL	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - hematocrit	Hematocrit, %	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - red blood cells	Red blood cells, 10^6/uL	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - white blood cells	White blood cells, 10^3/uL	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - platelets	Platelets, 10^3/uL	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - erythrocyte sedimentation rate	Erythrocyte sedimentation rate, mm per hour	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - lymphocytes	Lymphocytes, %	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - eosinophils	Eosinophils, %	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - monocytes	Monocytes, %	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - basophils	Basophils, %	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: complete blood count - neutrophils	Neutrophils, % (segmented and stab)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - total cholesterol	Total cholesterol in blood serum, mmol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - total protein	Total protein in blood serum, g/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - glucose	Glucose in blood serum, mmol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - creatinine	Creatinine in blood serum, umol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - alanine transaminase (ALT)	ALT in blood serum, U/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - aspartate transaminase (AST)	AST in blood serum, U/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - total bilirubin	Total bilirubin in blood serum, umol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - direct bilirubin	Direct bilirubin in blood serum, umol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - alkaline phosphatase (ALP)	ALP in blood serum, U/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: blood test results - urea	Urea in blood serum, mmol/L	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - color	Color of the urine (yellow, brown, etc.)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - transparency	Transparency of the urine (transparent/cloudy)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - specific gravity	Specific gravity of the urine	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - pH	pH of the urine	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - glucose	Glucose in the urine (mmol/L)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - protein	Protein in the urine (g/L)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - ketones	Ketones in the urine (mmol/L)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation
Secondary	Safety and Tolerability: urinalysis - urobilinogen	Urobilinogen in the urine (umol/L)	Screening, Day 29 or the early termination visit, whichever came first, within 44 days of study participation