Vitamin D to Improve Quadricep Muscle Strength

• ClinicalTrials.gov Identifier: NCT05174611
• Recruitment Status: Recruiting
• First Posted: January 3, 2022
• Last Update Posted: August 30, 2023
• Sponsor: Chinese University of Hong Kong
• Information provided by (Responsible Party): Prof. Tim-Yun Michael ONG, Chinese University of Hong Kong

Study Description

Brief Summary:

Quadriceps muscle strength is one of the key determinants for patients to fulfill the Return-to-Play (RTP) criteria after an anterior cruciate ligament reconstruction (ACLR), in which the muscle size is directly linked to muscle strength. Quadriceps muscle atrophy is unavoidable after ACLR, but the rehabilitation program should increase quadriceps muscle mass. However, despite good rehabilitation compliance, some patient's progress is sub-par and fail to regain muscle mass. Quadriceps muscle atrophy can persist beyond the completion of the rehabilitation program in almost half the patients and the reason behind this is still unknown. This represents an area that requires significant investigation, as quadriceps muscle atrophy and weakness have been shown to be determinants of poor knee function, decreased performance in sports and increased risk of reinjury.

Quadriceps muscle atrophy after ACLR is well documented. This can be due to a decreased ability to regain muscle mass with rehabilitation. Athletes are one of the high-risk groups for vitamin D insufficiencies. Vitamin D deficiency can potentially result in decreased hypertrophy when exercising the muscle, leading to a poorer outcome in rehabilitation. Vitamin D has long been recognized for its effect on musculoskeletal health. It can have a direct effect on muscle hypertrophy by acting on specific vitamin D receptors (VDRs) on myocytes, and sufficient or increased levels of vitamin D in patients have been found to correlate with an increase in the size, number, and strength of muscle fibres. Quadriceps muscle hypertrophy after ACLR is triggered by exercise training, facilitated by diet and a number of intrinsic factors. As the rehabilitation programs and diets are similar in patients with varying extents of quadriceps muscle atrophy, individual responses (intrinsic factors) to exercise training may account for the resulting persistent quadriceps muscle atrophy. In this study, the investigators hypothesize that the deficiency of vitamin D may contribute to persistent quadriceps atrophy and weakness.

With a stringent double-blinded randomized-controlled-trial (RCT) research design, our proposal will then address the research questions: 'Does vitamin D supplements improve the vitamin D deficiency status in patients after ACL reconstruction?', and 'Does vitamin D supplements improve quadriceps muscle strength for patients after ACLR?'

Condition or disease	Intervention/treatment	Phase
Anterior Cruciate Ligament Injuries; Quadriceps Muscle Atrophy; Anterior Cruciate Ligament Rupture; Anterior Cruciate Ligament Tear	Dietary Supplement: Vitamin D3; Other: Placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Participants will be assigned into either treatment or placebo groups
• Masking: Double (Participant, Care Provider)
• Masking Description: It is double blinded, subject will receive either the supplement or the placebo with same appearance and package. The lot number of the bottle will be used for randomization. And the investigators will ask the manufactory about it at the end of the study.
• Primary Purpose: Treatment
• Official Title: Vitamin D as an Intervention for Improving Quadricep Muscle Strength in Patients After Anterior Cruciate Ligament Reconstruction: A Randomized Double-Blinded, Placebo-Controlled Clinical Trial
• Actual Study Start Date: March 19, 2021
• Estimated Primary Completion Date: August 1, 2024
• Estimated Study Completion Date: August 1, 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment group; Subject in treatment group will receive one capsule of 2000IU Vitamin D3 supplement per day with the duration of 16 weeks.	Dietary Supplement: Vitamin D3; Subjects will receive 112 capsules with 4 bottles, 28 capsules in each bottle.
Placebo Comparator: Placebo group; Subject in placebo group will receive one capsule of placebo per day which looks exactly same as the Vitamin D3 capsule with the duration of 16 weeks.	Other: Placebo; Subjects will receive 112 capsules with 4 bottles, 28 capsules in each bottle.

Outcome Measures

Primary Outcome Measures :

1. Change of Isokinetic muscle strength [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   The dynamometer (Biodex System 4, Biodex Medical Systems Inc., New York, USA) will be used for measuring Isokinetic muscle strength in N. Subjects will perform a standardized warm-up exercise (5 min cycling) followed by the test. Concentric/concentric contractions of knee extension/flexion will be tested at 60°/s and 180°/s. Subjects will be seated on the dynamometer chair with their hips flexed to 85°.
2. Change of Biochemical Assays [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   Blood samples will be taken under non-fasting conditions. Serum / plasma obtained will be immediately stored at -80°C until analysis. Serum 25(OH) Vit-D assay: Serum 25(OH)Vit-D levels will be measured by commercial 25(OH) Vitamin D ELISA kit (Abcam ab213966) according to the manufacturer's instruction, providing the quantitative determination of 25(OH) Vitamin D3 and 25(OH) Vitamin D2. Sensitivity: 1.98 ng/ml (Range: 0.5 ng/ml - 1010 ng/ml).

Secondary Outcome Measures :

1. MRI Muscle thickness [ Time Frame: 4- & 8- months post operation ]
   Muscle volumes of quadricep muscle are measured using a 1.5 or 3.0 Tesla MRI Scanner. Axial (3mm thick cut) T1W images are obtained from the anterior superior iliac supine (ASIS) to patella. Quadriceps muscles were manually outlined in each axial slice. Muscle volume was calculated by summing all of the slice-multiplied by slice thickness. The quality of the muscle is assessed by analyzing the fat content of the muscle mass using technique that has been reported by Reeder et al (6). Bilateral legs will be performed before the start of the vitamin supplementation (4 months post-op) and with the injured side repeated after the completion of the 16-weeks supplementation (8 months postop).The uninjured side will be used as reference for 'normal volume'.
2. Ultrasound imaging muscle thickness [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   The Aixplorer® ultrasound system and a linear transducer probe with a bandwidth of 2-10 MHz were used to measure the muscle thickness of Vastus Medialis (VM), Vastus Lateralis (VL), and Rectus Femoris (RF) on both the injured and uninjured leg. Participants laid supine on a treatment table for the assessment. A measuring tape was used to locate VM, VL, RF and the patella by palpation, consequently marked with a pen for reference. RF was marked at 1/2 of the distance from the anterior superior iliac spine (ASIS) to the superior pole of the patella, VM was located at 1/5 of the distance away from the midpoint of the medial patella border to the ASIS, and VL was noted at 1/3 of the distance from the midpoint of the lateral patella border to the ASIS. After locating the anatomical points, excess contact gel was applied on these points. The transducer probe was aligned in the transverse plane and moved along the entire muscle bundle to capture a view of the VM, VL and RF.
3. Passive Knee laxity [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   To measure anterior-posterior knee laxity, the KT-1000 knee ligament arthrometer (MEDmetric Corp, San Diego, CA, USA) will be used. A manual force test will be applied until a 30lb sound signal is activated. Three trials will be performed. A side difference of 3 mm above is considered clinically relevant.
4. Change of BMI Anthropometric Measurement [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   Body Mass Index (BMI) in kg/m^2 would be calculated by the measured height and weight at 4 months post ACLR before vitamin D supplements, during the eighth week of vitamin D supplements, after the completion of 16 weeks vitamin D supplements, and 12-months post-operation.
5. Ground reaction force [ Time Frame: pre PEMF treatment , 4weeks, 8 weeks and 8 months after the commencement of intervention ]
   The Kinetic variables including vertical and horizontal ground reaction force (GRF) will be evaluated by a synchronized force plate at the centre of the capture volume at 1000Hz.
6. Knee Joint moments [ Time Frame: pre PEMF treatment , 4weeks, 8 weeks and 8 months after the commencement of intervention ]
   The kinematics will be assessed by the skin marker-based motion analysis system with the lower-body marker setup followed the OSTRC standard using 16-camera and 16 reflective skin marker during the single leg squat and single leg hop test.
7. Single leg hop distance [ Time Frame: 4weeks, 8 weeks and 8 months after the commencement of intervention ]
   The average of single leg hop distance in cm with three attempts will be measured during the single leg hop test.
8. Visual Analogue Scale [ Time Frame: Before and immediate after 1st - 16th of PEMF treatment ]
   The subjective measurement for chronic and acute pain will be recorded by the Visual Analogue Scale (VAS). VAS consists of a 10-cm line which represents the continuum between "painless" and "worst pain from 0 cm to 10 cm. The subject will be asked to draw a mark of it before and after each PEMF treatment session.
9. Tegner activity score [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
   This is an activity level scaled from 1 (low activity) to 10 (high activity).
10. International Knee Documentation Committee [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
    Consists of 10 questions on symptoms and activity ranging from 0 to 100 where 100 implies perfect knee function.
11. Lysholm knee scoring system [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
    Consists of eight items, total score ranging from 0 to 100 where higher scores indicate a better outcome with fewer symptoms or disability.
12. International Physical Activity Questionnaire [ Time Frame: Pre operation, 4-, 6- 8- and 12months post operation ]
    The level of physical activities during the past 7 days will be evaluated with a validated Chinese version of the quantitative physical activity questionnaire.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 40 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Aged 18-40 with unilateral ACL injury
2. Sporting injury with a Tegner score of 7
3. Pre-op serum vitamin D level <20 ng/ml
4. 4 months post-ACLR with serum Vitamin D level remained <20ng/ml
5. LSI for quadriceps strength <70% of contralateral leg at 4-month isokinetic assessment
6. Both knees without history of injury/prior surgery

Exclusion Criteria:

1. Concomitant bone fracture, major meniscus injury or full-thickness chondral injuries requiring altered rehabilitation program post-operatively
2. Pre-operative radiographic signs of arthritis
3. Metal implants that would cause interference on MRI
4. Non-HS graft for ACLR
5. Patient non-compliant to the rehabilitation program
6. Regular sunbed users

Contacts and Locations

Contacts

Contact: Michael Tim-Yun Ong; 26364171; michael.ong@cuhk.edu.hk

Locations

Hong Kong

The Chinese University of Hong Kong; Recruiting

Hong Kong, Hong Kong

Contact: Michael Tim-Yun Ong 26364171 michael.ong@cuhk.edu.hk

Sponsors and Collaborators

Chinese University of Hong Kong

  Study Documents (Full-Text)

Documents provided by Prof. Tim-Yun Michael ONG, Chinese University of Hong Kong:

Study Protocol  [PDF] March 1, 2021

Informed Consent Form  [PDF] March 1, 2021

More Information

• Responsible Party: Prof. Tim-Yun Michael ONG, Clinical Assistant Professor, Chinese University of Hong Kong
• ClinicalTrials.gov Identifier: NCT05174611
• Other Study ID Numbers: 2020.623
• First Posted: January 3, 2022
• Last Update Posted: August 30, 2023
• Last Verified: August 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: All IPD that underlie results in a publication
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: starting 6 months after publication
• Access Criteria: Journal reviewers

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Prof. Tim-Yun Michael ONG, Chinese University of Hong Kong:

ACL Reconstruction; Vitamin D; Quadricep muscle strength; Quadricep muscle atrophy

Additional relevant MeSH terms:

Muscular Atrophy; Atrophy; Rupture; Anterior Cruciate Ligament Injuries; Pathological Conditions, Anatomical; Wounds and Injuries; Knee Injuries; Leg Injuries; Neuromuscular Manifestations; Neurologic Manifestations; Nervous System Diseases; Vitamin D; Cholecalciferol; Vitamins; Micronutrients; Physiological Effects of Drugs; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents