Clinical trial NCT06379997: Oral Supplementation Compared With Hyaluronic Acid Infiltration in Rotator Cuff Tendinopathies
Official title: Efficacy of Oral Hyaluronic Acid and Collagen Supplementation Compared With Hyaluronic Acid Infiltration Treatment in Rotator Cuff Tendinopathies: A Prospective Study
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Tendinitis of Shoulder
Hyaluronic Acid
Dietary Supplements
Shoulder Pain
Lead sponsor: I.R.C.C.S. Fondazione Santa Lucia
Sponsor class: OTHER
First posted: 2024-04-23
Enrollment: 50
Sex: ALL
Minimum age (years): 30
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: The enrolled patients will be randomized in two groups: treated with oral supplements (Group 1 - G1) or with intra-articular hyaluronic acid (Group 2 - G2)
Primary purpose: TREATMENT

Brief summary: The present study aims to investigate the effectiveness of oral supplementation with a nutraceutical containing Collagen, Hyaluronic Acid, Vitamin C, and Manganese in functional outcome and pain reduction in cases of shoulder rotator cuff tendinopathy compared to a cycle of intra-articular hyaluronic acid injections.

The project involves the recruitment of 50 adult individuals presenting with shoulder pain and instrumental evidence of rotator cuff tendinopathy. All participants will receive one intra-articular injection of 1 ml of triamcinolone acetonide 40 mg. After the injection, participants will be divided into two groups according to Good Clinical Practice guidelines. One group will begin taking one vial per day for 56 days of an oral supplement containing Hyaluronic Acid, Collagen, Vitamin C, and Manganese (HA-COL) (Tendogenial®, B2Pharma) starting from the day following enrollment (Group 1). The other group will undergo a cycle of 3 intra-articular injections with hyaluronic acid (HA) (Hyalotend®, Fidia) (Group 2).

The hypothesis is that oral supplementation with HA-COL may have the same efficacy as intra-articular hyaluronic acid treatment in reducing pain and improving shoulder functionality.

Functional assessments will be conducted by a clinician unaware of the participants' group assignment. The following assessment scales will be used:

Numeric Rating Scale (NRS) for pain (from 0 to 10), evaluating 3 aspects of pain: 1) pain at rest, 2) nocturnal pain, 3) pain during movement.

Shoulder Disability Questionnaire (SDQ) for functionality.

Assessments will be conducted at the following time points:

T0) Before the administration of corticosteroid intra-articular injection (baseline).

T1) Seven days after the start of HA-COL intake for Group 1 and before the first intra-articular HA injection for Group 2 (T1, seven days from T0).

T2) At mid-cycle of oral HA-COL supplementation for Group 1 (28 days of intake) and seven days after the last HA injection for Group 2 (T2, 21 days from T1).

T3) Follow-up at 28 days from T2, at the end of the 56-day oral treatment cycle for Group 1, and 28 days after the last injection for Group 2 (T3, 56 days from T0).

Detailed description: Background Shoulder pain is a prevalent symptom primarily affecting the adult population, with an incidence of approximately 19 per 1000 and a prevalence ranging from 7 to 26%, particularly affecting women. The primary cause of shoulder pain is rotator cuff pathology, characterized by nocturnal pain and weakness, especially during external rotation and elevation movements of the shoulder, attributable to excessive loading on the cuff tissues. These symptoms often result in disability and functional impairment.

The etiology of rotator cuff pathology appears multifactorial, often associated with chronic age-related degeneration characterized by a reduced ability to synthesize collagen, increased levels of free radicals, and heightened catabolic activity (5). Tendinopathies exhibit widespread structural changes, including increased apoptosis of tenocytes, collagen fiber disintegration leading to a decrease in collagen type I, an increase in collagen type III resulting in a reversal of the collagen I/III ratio, and ineffective neoangiogenesis.

As tendinopathy primarily represents a degenerative condition where the inflammatory component plays a minor role, current therapeutic strategies mainly focus on regenerative approaches. While intra-articular cortisone therapy has historically been utilized to alleviate pain from rotator cuff injuries, its potential detrimental effect on tendon collagen limits its long-term efficacy, rendering cortisone therapy beneficial only in the short term.

Conversely, intra-articular treatment with hyaluronic acid (HA) for rotator cuff injuries appears promising in reducing pain and improving shoulder function. A recent review analyzed 11 studies encompassing a total of 1102 patients. Low to medium molecular weight hyaluronic acids were utilized in these studies, with infiltration performed either via anatomical landmarks or ultrasound guidance, targeting either intra-articular or subacromial sites. Moreover, rare minor side effects (such as pain at the injection site or slight vagal effects) were reported, with no instances of allergic reactions.

Hyaluronic acid (HA) is a carbohydrate, specifically a mucopolysaccharide, naturally present in all living organisms. When unbound to other molecules, it binds to water, imparting a rigid viscous 'jelly-like' quality. HA serves as an integral component of synovial fluid, crucial for joint chondroprotection, and constitutes a significant portion of the tendon extracellular matrix.

Upon injection into a joint, HA diminishes cytokine-induced responses and reduces synovial inflammation, ultimately relieving pain and enhancing joint function. Notably, preclinical in vitro and in vivo studies have demonstrated that exogenous peritendinous HA possesses the ability to inhibit fibroblast activity and diminish the proinflammatory M1 activation state of macrophages.

Observations of improved lubrication, chondroprotection, and enhanced synovial fluid characteristics have also been reported. Additionally, HA facilitates tenocyte regeneration, modulates the ratio of collagen type I/III, and mitigates apoptosis and impaired angiogenesis.

It is important to note that in most studies, HA was not injected directly into the degenerated tendon but rather near and/or into the joint space. While it can be speculated that alterations in synovial fluid may positively impact the tendon itself, it remains plausible that clinical improvement could be secondary to the favorable effects on concomitant arthrosis frequently associated with the condition.

Rationale for Dietary Supplementation of Collagen and HA:

Tendons primarily comprise cells, predominantly tenoblasts along with endothelial cells and some chondrocytes, as well as proteoglycans, notably decorin and hyaluronic acid, and collagen, primarily type I. The tendon exhibits a highly organized extracellular matrix wherein collagen molecules assemble into filamentous collagen fibrils (formed by microfibrils), which further aggregate to constitute collagen fibers, the principal structural components.

Various reviews have assessed the effectiveness of oral collagen supplementation in enhancing tendon structure. Particularly, a review highlights that some studies have demonstrated promising clinical implications of collagen peptide supplementation in the prevention and treatment of tendinopathies, although conclusive evidence is still lacking. Another review indicates that collagen supplementation alongside physical training significantly influences pain relief, increased cross-sectional area, and tendon thickness . From a joint perspective, collagen supplementation enhances mobility and functionality while reducing pain.

Oral supplementation of hyaluronic acid has predominantly been investigated for its effects on joints. For instance, it has been found effective in ameliorating pain and enhancing the quality of life in patients with knee arthrosis, with sustained effects observed at 2 months . Furthermore, the combined administration of HA and collagen orally has shown to improve functional recovery in patients following anterior cruciate ligament reconstruction, with evidence from resonance imaging indicating improved neoligament maturation.

Experimental design In order to conduct this study, we will recruit 50 patients with rotator cuff injuries from the outpatient clinic of the Santa Lucia Foundation. A physiatrist from the clinic, participating in the project, will explain the study to the enrolled individuals and obtain their informed consent.

The enrolled patients will undergo infiltrative treatment with corticosteroids (Triamcinolone acetonide 40 mg, 1 vial - Kenacort®, BRISTOL-MYERS SQUIBB S.r.l.).

The enrolled patients will be randomized in 2 groups: oral supplements (Group 1 - G1) or intra-articular hyaluronic acid (Group 2 - G2).

The Experimental Group (G1) will begin taking a supplement called Tendogenial® (B2Pharma S.r.l.) the day after enrollment. This supplement contains Collagen, Hyaluronic Acid, Vitamin C, and Manganese. Each day for 28 days, participants in G1 will consume one vial of Tendogenial®.

Group 2 (G2) will receive three intra-articular injections of Hyalotend® (Fidia), a viscous solution of sodium salt hyaluronic acid (500-730 kDa) obtained by bacterial fermentation in buffered saline. The injections will be administered without ultrasound guidance, using pre-filled 20 mg/2 ml syringes. The route of administration will be intra-articular via the posterior access route.

Participants will be advised to take only paracetamol as needed for pain relief. Additionally, they will be instructed not to undergo physiotherapy during the study period. Any participants who undergo physiotherapy or receive other analgesic therapies during the study will be excluded from the statistical analysis.

Inclusion Criteria:

Persistent shoulder pain lasting for at least 2 months, unresponsive to conservative treatment (nonsteroidal anti-inflammatory drugs \[NSAIDs\] and rehabilitation).

Ultrasound or MRI evidence of a rotator cuff lesion without complete tendon rupture.

Limited active range of motion (ROM) in the shoulder. Age between 30 and 80 years. Willingness to provide informed consent to participate in the study.

Exclusion Criteria:

Traumatic shoulder injury as the cause of pain. History of shoulder dislocation, fracture, or previous shoulder surgery. Presence of signs indicating ligamentous instability. Severe shoulder arthrosis, adhesive capsulitis, or calcific tendinitis. Previous infiltrative treatment with corticosteroids, hyaluronic acid, or collagen within the past 6 months.

Diagnosis of rheumatic or neoplastic diseases. Ongoing therapy with anticoagulants. Cervical radiculopathy. Pregnancy. History of heart, kidney, or liver failure. Cognitive impairment.

Both study groups will undergo assessment using pain and functional scales by a clinician who is blinded to the treatment group.

In addition to providing informed consent to participate in the study, participants will also sign a consent form specifically for infiltration, prepared by the Santa Lucia Foundation. Any adverse reactions or side effects experienced by participants will be documented and reported.

Eligibility criteria: Inclusion Criteria:

* Persistent shoulder pain lasting for at least 2 months unresponsive to conservative treatment (nonsteroidal anti-inflammatory drugs \[NSAIDs\] and rehabilitation)
* Ultrasound or MRI evidence of a rotator cuff lesion without complete tendon rupture
* Limited active range of motion (ROM) in the shoulder

Exclusion Criteria:

* Traumatic shoulder injury as the cause of pain
* History of shoulder dislocation, fracture, or previous shoulder surgery
* Presence of signs indicating ligamentous instability
* Severe shoulder arthrosis, adhesive capsulitis, or calcific tendinitis
* Previous infiltrative treatment with corticosteroids, hyaluronic acid, or collagen within the past 6 months
* Diagnosis of rheumatic or neoplastic diseases
* Ongoing therapy with anticoagulants
* Cervical radiculopathy
* Pregnancy
* History of heart, kidney, or liver failure
* Cognitive impairment

Primary outcomes:
measure: Numeric rating scale (NRS)
timeFrame: 1) (T0 - baseline). 2) Before the first administration of intra-articular HA for Group 2 and at seven days from the initiation of HA-COL for Group 1 (T1, seven days from T0). 3) At seven days fo
Secondary outcomes:
measure: Shoulder Disability Questionnaire (SDQ) for shoulder functionality
timeFrame: 1) (T0 - baseline). 2) Before the first administration of intra-articular HA for Group 2 and at seven days from the initiation of HA-COL for Group 1 (T1, seven days from T0). 3) At seven days fo
Other outcomes:
Locations:
city: Roma
country: Italy
facility: I.R.C.C.S. Fondazione Santa Lucia
state: RM
Study officials:
affiliation: I.R.C.C.S. Fondazione Santa Lucia, Roma, Italy
name: Stefano Brunelli, MD
role: STUDY_DIRECTOR
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