The goal of this clinical trial is to learn whether a natural marine supplement called NT-II™ (Salmon Undenatured Type II Collagen) can help lower knee discomfort caused by physical activity in otherwise healthy adults. Many active people experience knee pain when performing daily movements like climbing stairs, walking long distances, or squatting, even if they do not have a medical diagnosis such as arthritis. This discomfort can limit mobility, impact exercise routines, and reduce overall quality of life. This study is being conducted to determine whether NT-II™, taken as a once-daily oral supplement, can reduce this type of activity-related knee discomfort more effectively than a commonly used joint supplement containing glucosamine and chondroitin.

The main questions the study aims to answer are:

Does NT-II™ reduce knee discomfort caused by repeated activity over a 12-week period?

Does NT-II™ improve movement and quality of life compared to glucosamine-chondroitin?

Researchers will compare two different doses of NT-II™ (240 mg and 480 mg) to glucosamine (1500 mg) plus chondroitin (1300 mg), which is used as an active comparator. All three products will be taken once daily for 12 weeks.

Participants will:

Take their assigned supplement daily by mouth for 12 weeks

Track knee discomfort once per week using a pain rating scale called a visual analog scale (VAS) while doing an activity that usually causes discomfort, such as climbing stairs, walking, or squatting

Complete short surveys online about joint function, pain, and quality of life (including KOOS and SF-12 questionnaires)

Use a mobile app to perform simple knee range of motion tests at home

Wear a fitness tracker to monitor daily physical activity, such as step count and stair climbing

Collect two small blood samples at home using a finger-prick kit to check for changes in inflammation-related biomarkers

This study is for U.S.-based adults between the ages of 20 and 65 who are in generally good health but have had mild to moderate knee discomfort caused by physical activity for at least three months. The pain must be triggered by specific weight-bearing movements and be relieved by rest. Participants must not have osteoarthritis, rheumatoid arthritis, or other joint diseases. Individuals with recent knee injuries, major surgeries, or injections in the past six months cannot take part. Participants should not be using NSAIDs, turmeric, collagen, or other joint-related supplements during the study.

All study activities will take place remotely using a secure digital platform. There are no in-person clinic visits required. Eligible participants will receive all study materials by mail, including supplements, a wearable device, and an at-home blood sample collection kit. They will also be given access to a secure digital platform (Alethios) where they can complete questionnaires, enter pain ratings, and receive study instructions. Study staff will monitor progress, check for missing data, and assist participants through secure communication tools built into the platform.

The primary outcome of the study is the change in participant-reported knee discomfort, measured using a nominated activity VAS score (VASNA), from baseline to week 12. Additional outcomes will explore changes in function, mobility, physical activity, heart rate variability, and inflammatory biomarkers. The Pain Catastrophizing Scale (PCS) will also be used to examine whether thoughts and feelings about pain influence symptom reporting and treatment response.

This trial is sponsored by Hofseth BioCare ASA and is being conducted entirely online to improve access, lower participant burden, and support real-world understanding of joint health supplements. Study results may inform the use of NT-II™ as a marine-based nutritional strategy to support joint comfort in active individuals.

This is a decentralized, randomized, three-arm clinical trial evaluating the effects of NT-II™, a marine-derived undenatured type II collagen, on activity-related knee discomfort (ArKD) in otherwise healthy adults. The trial is sponsored by Hofseth BioCare ASA and conducted entirely virtually in the United States using the Alethios digital clinical trial platform.

Undenatured type II collagen has been studied for its role in promoting joint health, primarily through immune-mediated mechanisms that support oral tolerance and reduce inflammation in joint tissues. While the majority of existing evidence is based on UC-II®, derived from chicken sternum, NT-II™ offers a novel alternative derived from Norwegian Atlantic salmon (Salmo salar), embedded in a natural hydroxyapatite matrix. This study seeks to evaluate NT-II™ as a non-pharmacological intervention for individuals experiencing reproducible, activity-induced knee pain but without clinical joint disease.

Eligible participants are healthy U.S. adults aged 20 to 65, with body mass index (BMI) between 20.0 and 32.5 kg/m², who report activity-related knee discomfort of moderate intensity (VAS score 30-75 mm) for at least 3 months. Discomfort must be reliably triggered by specific knee-loading movements (e.g., stairs, squatting, walking) and relieved with rest. Individuals with clinically diagnosed osteoarthritis or recent joint injury are excluded.

Following screening and a one-week run-in period (with symptom tracking only), participants are randomized in a 1:1:1 ratio to receive one of three interventions for 12 weeks:

NT-II™ standard dose - 240 mg/day

NT-II™ high dose - 480 mg/day

Glucosamine (1500 mg) + Chondroitin (1300 mg) - active comparator

The primary endpoint is the change in self-reported knee discomfort on a participant-nominated visual analog scale (VASNA) - an activity-specific VAS ranging from 0 to 100 mm - from baseline to week 12. Participants nominate their most aggravating activity (e.g., stair descent), and VAS pain scores are collected weekly throughout the trial.

Secondary outcomes include:

Subscale scores from the Knee injury and Osteoarthritis Outcome Score (KOOS) questionnaire

Range of motion assessments (via the validated Curovate app)

Health-related quality of life (SF-12)

Daily activity metrics (e.g., step count, floors climbed) via wearable devices

Heart rate variability (HRV) recovery time as a biomarker of physiological resilience

Pain Catastrophizing Scale (PCS) to assess psychological contributors to pain reporting

The study is open-label, with centralized, blinded data analysis for biomarkers and PROMs. Outcome data are collected entirely remotely via the Alethios platform, wearable devices, mobile apps, and at-home blood collection kits.

This trial will assess both dose-response effects of NT-II™ and its comparative effectiveness versus glucosamine-chondroitin. It is designed to generate high-quality clinical evidence for NT-II™ in a functional knee discomfort population, while also exploring digital trial infrastructure, decentralized methodologies, and personalized symptom reporting frameworks. By integrating subjective and objective metrics, the study aims to enhance understanding of nutritional joint interventions in real-world settings.

Inclusion Criteria:

• Adults aged 20 to 65 years.
• Self-reported, reproducible knee discomfort associated with any knee-loading activities for at least 3 months prior to screening.
• Discomfort must occur in at least one knee during a nominated aggravating activity at least twice per week and subside with rest.
• VAS rating of 30 mm to 75 mm during the past week for the nominated activity.
• No current diagnosis of structural joint disease (e.g., osteoarthritis).
• Engages in physical activity involving knee-loading movements at least twice weekly for 20+ minutes.
• BMI between 20.0 and 32.5 kg/m².
• In good general health with no significant medical comorbidities.
• Able and willing to provide informed consent.
• Capable of completing study procedures remotely using mobile technology.

Exclusion Criteria:

• Persistent knee pain at rest or recent acute lower-limb trauma.
• Diagnosed structural or inflammatory joint disorders.
• Current or recent physiotherapy targeting knee pain (within 6 months).
• Allergy to fish or any study product ingredients.
• Scheduled lower-limb surgery during the study period.
• Other musculoskeletal disorders affecting ambulation.
• Recent joint injections (within 3 months).
• Use of joint supplements in the past 3 months.
• Use of analgesics ≥3 days/week in the past 3 months.
• NSAIDs/acetaminophen use is permitted with restrictions:
• Not within 24 hours of blood sampling or VAS assessments.
• Must be documented.
• Chronic use of medications that affect musculoskeletal symptoms (e.g., muscle relaxants, gabapentinoids) unless infrequent (≤2x/week) and not within 24 hours of assessments.
• Regular use of PPIs (>3x/week in past month).
• Systemic corticosteroids, immunosuppressants, or opioids within 4 weeks.
• Unstable weight or significant recent dietary changes.
• Significant medical conditions (e.g., cancer, hepatic/renal impairment, CVD, thyroid disease, diabetes).
• Neurological, cognitive, or psychiatric disorders affecting participation.
• Use of tobacco/nicotine or other substances.
• Diagnosed sleep disorders.
• Strict vegan diet or sedentary lifestyle.
• Inability to swallow capsules.
• Pregnant, breastfeeding, or planning pregnancy.
• Women of childbearing potential not using contraception.
• Participation in another interventional clinical trial.

Individual participant data (IPD) will not be shared due to the proprietary nature of the intervention, data privacy considerations related to remote monitoring technologies, and the absence of a pre-specified data sharing agreement. The sponsor may consider future data sharing requests on a case-by-case basis in accordance with applicable privacy regulations and scientific relevance.