Efficacy and Safety Comparison of Herbal Medicinal Products in Acute Bronchitis: Liquid Extract from Thyme Herb, Primrose Root Tincture, and Ivy Leaf Extract

The primary objective of this randomized, controlled, open-label, multi-center trial is to assess the **non-inferiority** of a test herbal medicinal product compared to two reference products in terms of the change in the **Bronchitis Severity Score (BSS)** in patients with **acute bronchitis** after 7 days of treatment. This evaluation is clinically relevant as it aims to establish the test product's effectiveness in managing symptoms of acute bronchitis, a common respiratory condition.

Secondary objectives include:

• Assessment of the superiority of the test product versus each reference product regarding the change in BSS after 7 days of treatment.
• Descriptive evaluation of differences in the change of BSS between the test product and each reference product over the entire observation period.
• Descriptive evaluation of differences in **cough severity (CS)** using the Visual Analogue Scale (VAS) and Verbal Category Descriptive (VCD) score between the test product and each reference product over the observation period.
• Descriptive evaluation of the global efficacy of all treatments assessed at specific post-baseline visits by both patients and investigators.
• Descriptive evaluation of the safety of all treatments, including adverse events, and the global tolerability of all treatments assessed at specific post-baseline visits by both patients and investigators.

The clinical trial involves participants diagnosed with **acute bronchitis**. The study population includes both male and female patients, aged between 18 and 75 years, who are in a generally good state of health aside from their bronchitis condition. The sponsor has not provided the total number of participants. Participants were selected based on their ability to understand and willingness to adhere to the study rules, as well as their consent to participate. The trial includes individuals from any ethnic origin, with symptoms of acute bronchitis present for 48-72 hours prior to treatment. Participants are required to have a Bronchitis Severity Score (BSS) of at least 10 points and a CS score of at least 50 mm on the 100 mm VAS at the initial visit. Additionally, a VCD score of at least 2 points is necessary at the first visit. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, controlled, open-label, multi-center study to evaluate the efficacy and safety of three herbal medicinal products in the treatment of **acute bronchitis**. The trial aims to assess the non-inferiority of the test product compared to two reference products by measuring changes in the Bronchitis Severity Score (BSS) over a 7-day treatment period. The study will involve male and female participants aged 18 to 75 years who have experienced symptoms of acute bronchitis for 48-72 hours prior to treatment. Participants must be in good health, aside from the bronchitis, and must provide written informed consent.

The trial will commence with a screening visit (V1) to confirm eligibility based on inclusion criteria, including a BSS of at least 10 points and a CS score of at least 50 mm on a 100 mm Visual Analogue Scale (VAS). Following the baseline assessment, participants will be randomly assigned to receive one of the three oral liquid formulations for a maximum treatment period of 7 days. The primary endpoint is the change in BSS from baseline (V1) to the end of treatment (V6). Secondary endpoints include changes in BSS and CS scores at each post-baseline visit (V2 to V8) and the area under the curve (AUC) for these scores.

Study visits are scheduled as follows: the initial screening and baseline visit (V1), followed by post-baseline visits on days 2 (V2), 3 (V3), 4 (V4), 5 (V5), 6 (V6), 7 (V7), and a final visit on day 8 (V8). Each visit will involve assessments of BSS, CS, and VCD scores, as well as evaluations of global efficacy using a 5-point Likert scale. The expected duration of participant involvement is approximately 8 days, with the possibility of early termination if adverse events or protocol violations occur.

The trial is anticipated to start recruitment on January 18, 2024, and is expected to conclude by June 30, 2024. Participants will be monitored closely throughout the study to ensure safety and adherence to the protocol. The trial is classified as a Phase IV study, as all products have existing marketing authorizations and are used according to their respective Summary of Product Characteristics (SmPc).

The clinical trial involves the administration of three herbal medicinal products, each formulated as **oral liquid**. The first experimental medication is **Bronchicum Tropfen**, which contains a **liquid extract from thyme herb** (DER 1:2-2.5) and **primrose root tincture**. The extraction solvents for the thyme herb include ammonia solution 10% (m/m), glycerol 85%, ethanol 90%, and water in a ratio of 1:20:70:109. The primrose root tincture is extracted using ethanol 50% (v/v). The maximum daily dose is 175 drops, with a total maximum dose of 1225 drops over a treatment period of 7 days. The medication is administered orally.

The second product, **Bronchipret® Tropfen**, is used as a comparator in the study. It contains a **fluid extract from ivy leaves** (1:1) and **thyme herb fluid extract** (1:2-2.5). The ivy leaves are extracted using ethanol 70% (v/v), while the thyme herb uses the same extraction solvents as Bronchicum Tropfen. The maximum daily dose is 7.8 ml, with a total maximum dose of 54.6 ml over 7 days. This medication is also administered orally.

The third product, **Prospan® Hustentropfen**, serves as another comparator. It contains a **dry extract of Hederae folium** (5-7.5:1), with ethanol 30% (m/m) as the extraction solvent. The maximum daily dose is 72 drops, with a total maximum dose of 504 drops over the 7-day treatment period. This product is administered orally.

All three products are administered for a maximum treatment period of 7 days, with compliance monitored through dosing schedules. The trial aims to assess the non-inferiority of the test product compared to the two comparator products in terms of efficacy and safety in treating acute bronchitis.

Efficacy in this clinical trial will be assessed by evaluating the change in the **Bronchitis Severity Score (BSS)** in patients with acute bronchitis. The primary endpoint is the change in BSS between the baseline visit (V1) and visit V6, which occurs after 7 days of treatment. Secondary endpoints include the change in BSS between the baseline and each post-baseline visit (V2, V3, V4, V5, V7, and V8), as well as the baseline-adjusted area under the curve (AUC) for BSS. Additionally, the **Cough Severity (CS)** will be assessed using a visual analog scale (VAS) between the baseline and post-baseline visits, with AUCs generated from these VAS values. The change in CS assessed by the **Verbal Category Descriptor (VCD) score** between the baseline and each post-baseline visit will also be evaluated. Global efficacy will be measured using scores from a 5-point Likert scale by both the patient and investigator at post-baseline visits V6, V7, and V8.