NT-II™ Collagen for Joint Discomfort and Function

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.