Trial Outcomes & Findings for Clinical Study to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% in the Treatment of Tinea Pedis (NCT NCT03824912)

Last Updated: 2019-06-27

Results Overview

Equivalence: Per-Protocol Population Therapeutic Cure: To be considered a Therapeutic Cure, the patient must have both Clinical and Mycological Cure of tinea pedis. Therapeutic Failure: A patient will be considered a Therapeutic Failure if: 1. the patient is a Clinical or Mycological Failure 2. the patient was considered to have an insufficient therapeutic response 3. the patient used topical drug therapy for irritation or pruritus on the feet after the treatment phase of the study

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

831 participants

Primary outcome timeframe

Two weeks after the end of treatment (Day 56 ± 4) (Equivalence)

Results posted on

2019-06-27

Participant Flow

Participant milestones

Participant milestones
Measure	Test: Ketoconazole Cream 2% Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Overall Study STARTED	332	335	164
Overall Study COMPLETED	192	201	96
Overall Study NOT COMPLETED	140	134	68

Reasons for withdrawal

Reasons for withdrawal
Measure	Test: Ketoconazole Cream 2% Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Overall Study Lost to Follow-up	18	15	8
Overall Study Negative Baseline Culture Result	118	112	57
Overall Study Non-Compliance with Study Drug	0	0	1
Overall Study Protocol Violation	1	4	1
Overall Study Withdrawal by Subject	3	2	1
Overall Study Participation in another study	0	1	0

Baseline Characteristics

Clinical Study to Evaluate the Therapeutic Equivalence of Ketoconazole Cream 2% in the Treatment of Tinea Pedis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Test: Ketoconazole Cream 2% n=314 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=319 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) n=156 Participants Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Total n=789 Participants Total of all reporting groups
Age, Continuous	45.6 years STANDARD_DEVIATION 13.6 • n=5 Participants	46.7 years STANDARD_DEVIATION 13.9 • n=7 Participants	44.8 years STANDARD_DEVIATION 14.4 • n=5 Participants	45.9 years STANDARD_DEVIATION 13.9 • n=4 Participants
Sex: Female, Male Female	131 Participants n=5 Participants	114 Participants n=7 Participants	64 Participants n=5 Participants	309 Participants n=4 Participants
Sex: Female, Male Male	183 Participants n=5 Participants	205 Participants n=7 Participants	92 Participants n=5 Participants	480 Participants n=4 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	154 Participants n=5 Participants	153 Participants n=7 Participants	75 Participants n=5 Participants	382 Participants n=4 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	160 Participants n=5 Participants	166 Participants n=7 Participants	81 Participants n=5 Participants	407 Participants n=4 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	147 Participants n=5 Participants	153 Participants n=7 Participants	74 Participants n=5 Participants	374 Participants n=4 Participants
Race (NIH/OMB) White	166 Participants n=5 Participants	163 Participants n=7 Participants	80 Participants n=5 Participants	409 Participants n=4 Participants
Race (NIH/OMB) More than one race	1 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	5 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants

PRIMARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Equivalence)

Population: The Per-Protocol population was used for this analysis to determine equivalence between the Test and Reference groups only. To determine equivalence, only the test and reference treatment arms are analyzed.

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=184 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=191 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Primary Efficacy Endpoint: The Number of Patients in Each Treatment Group With a Therapeutic Cure of Tinea Pedis (Equivalence: Per-Protocol Population)	89 Participants	90 Participants	—

PRIMARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Superiority)

Population: The MITT Population was used for analysis.

Superiority: modified Intent-to-Treat Population Therapeutic Cure: To be considered a Therapeutic Cure, the patient must have both Clinical and Mycological Cure of tinea pedis. Therapeutic Failure: A patient will be considered a Therapeutic Failure if: 1. the patient is a Clinical or Mycological Failure 2. the patient was considered to have an insufficient therapeutic response 3. the patient used topical drug therapy for irritation or pruritus on the feet after the treatment phase of the study

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=195 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=199 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) n=97 Participants Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Primary Efficacy Endpoint: The Number of Patients in Each Treatment Group With a Therapeutic Cure of Tinea Pedis (Superiority: Modified Intent-to-Treat Population)	92 Participants	94 Participants	26 Participants

SECONDARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Equivalence)

Clinical Cure: To be considered a clinical cure the patient's total severity score must be ≤ 2 with no individual severity score \> 1. Clinical Failure: A patient will be considered a Clinical Failure if the patient's total severity score is \> 2 or any individual score is \> 1. Local Signs and Symptoms The most severely affected area will be identified as the target lesion at the baseline visit and will be used for the assessments at Day 42 and Day 56 visits. The Clinical Signs and Symptoms of tinea pedis will be rated by the Investigator as "none", "mild," "moderate" or "severe" using the following standardized rating scale. 0 = None (complete absence of any sign or symptom) 1. = Mild (Slight) 2. = Moderate (Definitely Present) 3. = Severe (Marked, Intense) The following signs and symptoms will be rated at each visit: * Signs: Fissuring/cracking, erythema, maceration, and scaling * Symptoms: Pruritus and burning/stinging

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=184 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=191 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Secondary Efficacy Endpoint: The Number of Patients in Each Treatment Group With a Clinical Cure of Tinea Pedis (Equivalence: Per-Protocol Population)	97 Participants	110 Participants	—

SECONDARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Equivalence)

Population: The PP population was used for this analysis to determine equivalence between the Test and Reference groups only. One patient had an inconclusive result for the fungal culture at Visit 3 and was excluded from the analysis of the secondary endpoint for the mycological cure. Patient was a clinical failure and was included in the primary analysis.

Mycological Cure: To be considered a mycological cure the patient must have a negative Potassium hydroxide (KOH) test and a negative fungal culture. Mycological Failure: A patient will be considered a Mycological Failure if the patient's KOH test is positive or the patient's fungal culture is positive.

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=184 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=190 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Secondary Efficacy Endpoint:The Number of Patients in Each Treatment Group With a Mycological Cure of Tinea Pedis (Equivalence: Per-Protocol Population)	127 Participants	118 Participants	—

SECONDARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Superiority)

Population: The MITT population was used for analysis.

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=195 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=199 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) n=97 Participants Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Secondary Efficacy Endpoint: The Number of Patients in Each Treatment Group With a Clinical Cure of Tinea Pedis (Superiority: Modified Intent-to-Treat Population)	100 Participants	116 Participants	35 Participants

SECONDARY outcome

Timeframe: Two weeks after the end of treatment (Day 56 ± 4) (Superiority)

Population: The MITT population was used for the analysis. One patient had an inconclusive result for the fungal culture at Visit 3 and was excluded from the analysis of the secondary endpoint for the mycological cure. Patient was a clinical failure and was included in the primary analysis.

Outcome measures

Outcome measures
Measure	Test: Ketoconazole Cream 2% n=195 Participants Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=198 Participants Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) n=97 Participants Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Secondary Efficacy Endpoint:The Number of Patients in Each Treatment Group With a Mycological Cure of Tinea Pedis (Superiority: Modified Intent-to-Treat Population)	132 Participants	122 Participants	39 Participants

Adverse Events

Test: Ketoconazole Cream 2%

Serious events: 0 serious events

Other events: 12 other events

Deaths: 0 deaths

Reference: Ketoconazole Cream 2%

Serious events: 0 serious events

Other events: 15 other events

Deaths: 0 deaths

Placebo: Cream (Test Vehicle)

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Dr. Lalatendu Panigrahi, Chief Scientific Officer

Encube Ethicals Pvt Ltd

Phone: +91-22-6264-7002

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee In the Clinical Trials Agreements between the sites and the Contract Research Organization, sites are instructed that the Investigator shall not publish, or seek to publish, either in whole or in part any results of the Study without the written consent.
Publication restrictions are in place

Restriction type: OTHER

Measure	Test: Ketoconazole Cream 2% n=314 participants at risk Test: Ketoconazole Cream 2% (Encube Ethicals Pvt Ltd) Ketoconazole Cream 2%: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Reference: Ketoconazole Cream 2% n=319 participants at risk Ketoconazole Cream 2% (G\&W Laboratories Inc.; Registrant: Teva Pharmaceuticals USA Inc.) Ketoconazole Cream 2% (G\&W Laboratories Inc.): Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.	Placebo: Cream (Test Vehicle) n=156 participants at risk Placebo Cream (Test vehicle) (Encube Ethicals Pvt Ltd) Placebo: Patients will be instructed to apply sufficient study product to cover affected and immediate surrounding areas once daily for 42 ± 4 days. Each patient is expected to receive 42 ± 4 doses.
Gastrointestinal disorders Diarrhoea	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.31% 1/319 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Gastrointestinal disorders Dyspepsia	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.31% 1/319 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Gastrointestinal disorders Gastritis	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Gastrointestinal disorders Toothache	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Infections and infestations Nasopharyngitis	1.3% 4/314 • Number of events 4 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	1.3% 4/319 • Number of events 4 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Infections and infestations Upper respiratory tract infection	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Injury, poisoning and procedural complications Arthropod bite	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.31% 1/319 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Injury, poisoning and procedural complications Contusion	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.31% 1/319 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Investigations Blood pressure increased	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Musculoskeletal and connective tissue disorders Back pain	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.63% 2/319 • Number of events 2 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Musculoskeletal and connective tissue disorders Joint swelling	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.63% 2/319 • Number of events 2 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Musculoskeletal and connective tissue disorders Pain in extremity	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.63% 2/319 • Number of events 2 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Nervous system disorders Headache	0.96% 3/314 • Number of events 3 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	1.6% 5/319 • Number of events 6 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Reproductive system and breast disorders Adnexa uteri pain	0.00% 0/314 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.64% 1/156 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Reproductive system and breast disorders Dysmenorrhoea	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.
Skin and subcutaneous tissue disorders Blister	0.32% 1/314 • Number of events 1 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/319 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.	0.00% 0/156 • 5 months The "Total Number of Participants at Risk" is not consistent with the numbers provided in any of the rows in the Participant Flow module, since the Overall Summary of Adverse Events is based on the Safety Population. The Safety population will include all randomized patients who use at least one dose of product.