A two part, randomized, participant and investigator-blinded, 2-arm, parallel-design, placebo-controlled study to evaluate the safety, tolerability and preliminary efficacy of NGI226 microparticles on tendon regeneration in patients with Achilles tendinopathy

The primary objective of this study is to evaluate the **local and systemic safety** and tolerability of a single peritendon injection of NGI226 microparticles in patients with mid-portion **Achilles tendinopathy**. This is clinically relevant as it aims to ensure that the treatment does not cause adverse effects, which is crucial for patient safety and the potential for future therapeutic use.

Secondary objectives include assessing the effects of a single peritendon injection of NGI226 microparticles versus placebo on the restoration of biomechanical integrity of the **Achilles tendon**. This evaluation is important for understanding the potential efficacy of NGI226 in improving tendon function and structure, which could lead to enhanced treatment options for patients suffering from this condition.

The clinical trial involves a total of **20 participants** diagnosed with **Achilles Tendinopathy**. The study population comprises adults aged between **30 to 70 years**, inclusive of both **male and female** subjects. Participants were selected based on the presence of clinically and imaging-diagnosed mid-portion Achilles tendinopathy, with symptoms persisting for at least 8 weeks but less than 12 months. The condition must have been refractory to at least 6 weeks of conservative treatment, including physiotherapy, NSAIDs, and RICE. The trial includes a vulnerable population, indicating that special considerations are in place to ensure their safety and well-being. Participants' general health status is not specified beyond the inclusion criteria, and no specific lifestyle considerations such as diet or physical activity are mentioned. The selection process required obtaining written informed consent prior to any study-specific screening procedures.

The clinical trial is designed as a **randomized**, participant and investigator-blinded, two-arm, parallel-design, placebo-controlled study. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of NGI226 microparticles in patients with **Achilles Tendinopathy**. The trial is divided into two parts and is expected to conclude by June 2025, with recruitment having commenced in July 2023. Participants will be randomly assigned to receive either NGI226 or a placebo, both administered as a single peritendon injection. The study will assess local and systemic safety, including treatment-emergent adverse events, local tolerability, laboratory tests, electrocardiogram parameters, and vital signs. Secondary endpoints include changes in tendon stiffness from baseline at week 12, assessed by ultrasound-based shear wave elastography.

Participants will undergo a series of study visits, beginning with a screening visit to confirm eligibility based on criteria such as age, clinical diagnosis, and previous treatment history. The inclusion criteria require participants to be adults aged 30 to 70 years, with symptoms present for at least eight weeks but less than 12 months, and refractory to at least six weeks of conservative treatment. Following the screening, eligible participants will be enrolled and randomized. Subsequent visits will include follow-up assessments to monitor safety and efficacy outcomes, with the final visit marking the end of the study. The expected duration of participant involvement is approximately 12 weeks, with conditions for early termination including withdrawal of consent or the occurrence of serious adverse events.

The clinical trial involves the administration of **NGI226**, a powder for suspension for injection, developed by Novartis Pharma AG. The active substance, NGI226, is of chemical origin. The pharmaceutical form is specifically designed for infiltration, with a maximum daily dose of 120 mg. The treatment involves a single peritendon injection, with the primary objective of assessing the local and systemic safety and tolerability in patients with mid-portion Achilles tendinopathy. The dosing schedule is structured to ensure that the maximum total dose does not exceed 120 mg over the treatment period, which is limited to one day. Participant compliance will be monitored through standard clinical trial procedures to ensure adherence to the dosing regimen.

The study also includes a **placebo** group, which receives a placebo formulation designed to match the NGI226 treatment. The placebo is a powder for suspension for injection, intended to mimic the appearance and administration route of the active treatment. This placebo control is essential for maintaining the integrity of the double-blind study design, allowing for an unbiased evaluation of the safety and efficacy of NGI226. The placebo is administered via infiltration, following the same protocol as the active treatment, to ensure consistency across study arms. Compliance with the placebo administration is monitored in the same manner as the active treatment group.

Efficacy in this clinical trial will be assessed through both primary and secondary endpoints. The primary endpoints include the evaluation of local and systemic treatment Emergent Adverse Events (TEAEs) and serious TEAEs, as well as local tolerability indicators such as changes in pain, swelling, redness, warmth, range of motion, itching, infection, and tendon physical examination. Additionally, laboratory tests will be conducted, including clinical chemistry, hematology, coagulation, **Liver Function Test (LFT)**, and urinalysis. Electrocardiogram parameters (ECGs) and vital signs, including blood pressure, pulse rate, and body temperature, will also be monitored.

The secondary endpoint focuses on changes in tendon stiffness from baseline at week 12, which will be assessed using ultrasound (US)-based shear wave elastography (SWE). This method provides a quantitative measure of tendon stiffness, offering insights into the efficacy of the treatment in promoting tendon regeneration in patients with Achilles tendinopathy. The assessments are scheduled to occur at specific timepoints, with the primary focus on the 12-week mark to evaluate the changes from baseline effectively.