A comparative study of the efficacy of different doses of platelet-rich plasma in the treatment of Degree I and Degree II knee meniscus injury in young adults: Study protocol for a prospective, single-center, three-blind, randomized controlled trial

doi:10.21203/rs.3.rs-2868346/v1

Background:

Grade I and II knee meniscus injuries in young people account for a relatively large proportion of sports injuries. If not cured in time, it may seriously affect the quality of life and even cause disability.Studies have shown that platelet-rich plasma (PRP) is effective in the treatment of knee meniscus injury, but the optimal therapeutic dose of PRP has not been regulated and clarified in current relevant guidelines or expert consensus.This study intends to use a randomized controlled trial to compare and analyze the efficacy and safety of 2ml, 5ml and 8ml PRP in the treatment of meniscus injury of knee joint, so as to provide evidence-based medical evidence for improving the clinical guidelines for the treatment of meniscus injury with PRP.

Methods/design:

This study is a one-year prospective single-center triple-blind randomized controlled trial. Patients who meet the inclusion criteria are randomly divided into the experimental group and the control group. The experimental group is set as the PRP treatment group, and the control group is set as the placebo group. The treatment of all patients will last for 5 weeks and follow-up for 6 months.The experimental group and the control group plan to evaluate Lysholm knee score, MRI (including T2mapping technology) and other main observation indicators.And visual analog scale (Visual analogue scale, VAS), quality of life score(36-item Short Form Health Survey, SF-36), muscle Bone ultrasound, infrared thermal imaging,incidence of adverse reactions and other secondary observation indicators are used to compare the curative effects.All these results will be analyzed at the end of the trial Analysis.

Discussion:

There is no uniform standard for the dose of PRP in the treatment of meniscus injury, and there is no literature report on whether there are differences in efficacy and safety among several commonly used doses in clinical practice. This study explores the clinical appropriate dose of PRP in the treatment of meniscus injury of knee joint of young people in degree I and II,which provides a scientific basis for the optimization of the treatment of meniscus injury, and provides evidence-based medical evidence for the revision and improvement of PRP treatment guidelines for meniscus injury.

Trial Registration: China Clinical Trial Registration: ChiCTR2200057591, November 14,2022

Experimental Ethics: 2022EC1-008

meniscus injury

platelet-rich plasma therapy

dose

efficacy

randomized controlled trial

With the increase of young people participating in sports, the incidence of meniscus injury increase year by year and tend to be younger. The survey shows that the incidence of meniscus injury in American high school athletes is 5.1/100 000[1]. There are about 50 million patients with meniscus injury in China, and the prevalence rate of meniscus in sports injury is about 5% [2]. Such patients tend to have a very low referral rate, and often turn into chronic injuries leading to joint pain, swelling, limited activity, even lameness,limited flexion and extension function in serious cases.At present, conservative treatment is mainly used for meniscusⅠandⅡinjuries, and arthroscopic surgery or excision is mostly used for meniscus Ⅲ injuries. However, no matter what kind of treatment mentioned above, the medical problem of meniscus tissue repair and regeneration can not be solved.Treatment of Platelet-rich plasma (PRP) offers a convenient and effective way to repair and regenerate damaged tissue of meniscus. Relevant studies at home and abroad [3–12] suggest that PRP is effective in the treatment of meniscus injury, but the dose of PRP used is quite different, and there is no unified standard of therapeutic dose. However, the "chaos" of PRP treatment is more prominent in clinical practice, with the occurrence of inconsistent dose, inconsistent course of treatment and non-standard preparation. This may result in uneven meniscus repair and incomparable therapeutic effects. Due to the lack of high-quality literature or/and expert consensus, guidelines and other support, there is no relatively standardized standard for PRP treatment of meniscus injury in actual clinical work.

Trial objectives

The main purpose of this study is to compare and analyze the efficacy and safety of 2ml, 5ml and 8ml PRP in the treatment of knee meniscus injury by using randomized controlled trials, and to explore the clinical appropriate dose of PRP in the treatment of knee meniscus injury with both efficacy and safety.It is helpful to optimize the clinical program of PRP treatment of knee meniscus injury, and can provide evidence-based medical evidence for improving related clinical guidelines.

Trial design

This is a prospective, single-center, three-blind, randomized controlled clinical trial.Table 1 shows the overview of the trial methods and design.

Table 1 Chinese clinical Trial Registry data set

Data category

Information

Primary registry and trial identifying number

Date of registration in primary registry

Date of Last Refreshed on

Registration Status

Source(s) of funding

Primary sponsor and Secondary sponsor

Contact for scientific queries

Public title

Scientific title

Countries of recruitment

Target disease

Study type

Objectives of Study

Intervention(s)

Key inclusion and exclusion criteria

Target sample size

Recruitment status

Primary outcome(s)

Key secondary outcomes

Chinese Clinical Trial Registry number:ChiCTR2200057591

15/03/2022

14/11/2022

1008001 Prospective registration

Department of Rehabilitation Medicine,General Hospital of Western Theater Command

N/A

CC,[email protected]

Comparative study of different doses of platelet-rich plasma in the treatment of meniscus injury of grade I and II knee joint in young people

China

Knee meniscus injury

Observational study

To explore the clinical appropriate dose of PRP in the treatment of meniscus injury of knee joint in young people

PRP treated low(2ml), medium(5ml) and high(8ml) dose intervention groups

The placebo group was plasma

Ages eligible for study: 18-44yr

Sexes eligible for study: both

Inclusion criteria:1. Patients in line with clinical diagnosis and MRI shows meniscus injury of degree Ⅰ and Ⅱ;2. Young people aged 18 to 44 with full capacity for civil conduct should be selected;3. Hb > 120g/L, PLT > 120*10^9/L;4. The coagulation function and transmission of nine normal;5. Subjects do not take glucosamine hydrochloride and other drugs to protect articular cartilage or received injection of sodium hyaluronate within 3 months before the test;6. Subjects and their families are informed of the research content and voluntarily sign relevant agreements.

(1) Exclusion criteria：1. Those who do not cooperate with the study;2. Patients with serious articular cartilage injury and cruciate ligament injury without repair or reconstruction;3. Injection site infection;4. Sepsis;5. Patients with dysfunction of important organs such as heart, liver and kidney;6.Patients with complicated immunodeficiency or severe infection; 7.Non-steroidal anti-inflammatory and analgesic drugs have not been stopped for more than 48 hours;8. Hematopoietic system or skeletal system tumors;9.Systemic corticosteroid treatment is not stopped for more than 2 weeks.

84

Recruiting

Lysholm scale,MRI(including T2mapping technology)

VAS,SF-36,infrared thermal imaging,musculoskeletal ultrasound

Trial setting

General Hospital of Western Theater Command is used as the test base in this experiment, which is a large comprehensive Grade-A hospital integrating medical treatment, teaching, scientific research and health management.The rehabilitation medicine discipline the researchers work in is the key discipline of the State Administration of Traditional Chinese Medicine, the Paraplegia Diagnosis and Rehabilitation Center of the whole Army, the Clinical Medical Research Center of Orthopedics and Sports Rehabilitation of Traditional Chinese Medicine of Sichuan Province and the quality specialty of Lianqin Medicine, which has a good research foundation.The relevant medical staff involved have carried out PRP treatment for more than 4 years, accepted at least nearly 1,000 patients, and have mastered the key technology of PRP treatment. Training on standardized registration, randomization, rehabilitation intervention, evaluation and data collection is also conducted.

Eligibility criteria

The target population for this study are those who met the consolidated inclusion criteria:

According to the 2018 edition of "BASK National Consensus" [13] diagnostic criteria, and MRI diagnosis of meniscus injury Ⅰ, Ⅱ degree injury;
According to WHO "Age Division Criteria", young people aged 18 to 44 with full capacity for civil conduct should be selected;
Hb＞120g/L，PLT＞120×10⁹ /L[14] ;
The coagulation function and transmission of nine normal;
Subjects do not take glucosamine hydrochloride and other drugs to protect articular cartilage or received injection of sodium hyaluronate within 3 months before the test;
Subjects and their families are informed of the study content and voluntarily sign the relevant agreement.

The exclusion criteria are as follows[15] :

Those who do not cooperate with this study;
Patients with serious articular cartilage injury and cruciate ligament injury without repair or reconstruction;
Patients with degree III meniscus injury undergoing surgery or (and) without surgery;
Abnormal coagulation function: platelet dysfunction syndrome, thrombocytopenia, hemorrhagic disease, etc.
Injection site infection;
Sepsis;
Patients with heart, liver, kidney and other important organ dysfunction;
Patients with complicated immunodeficiency or severe infection;
Non-steroidal anti-inflammatory and analgesic drugs have not been stopped for more than 48 hours;
Hematopoietic or skeletal system tumors;
Hb＜100g/L，PLT＜105×10⁹/L；
Systemic corticosteroid therapy is discontinued for less than 2 weeks.

Recruitment, randomization and allocation

The patients who may be qualified are initially screened by rehabilitation doctors through consultation, physical examination and check. The commissioner guides the patient to prepare according to the trial procedure.

The SPSS software is used for random grouping.Because patients tend to be enrolled one after another,therefore, before the start of the experiment, patients will be randomly assigned to different groups according to the enrollment order of patients and the corresponding random number, and the grouping is hidden.Once the trial is initiated, patients who meet the inclusion criteria can be directly enrolled into the corresponding group according to the pre-determined protocol.Eligible patients are provided with informed consent that explained in detail the significance of the trial, the process of randomization, inconsistent rehabilitation protocols, treatment procedures, and possible adverse effects.Those who agree will sign consent forms as required by the Ethics Committee and in accordance with the "Declaration of Helsinki".Figure 1 shows an overview of recruitment, random allocation, and allocation based on the CONSORT principle.

Blinding

The plasma placebo group has the same color and appearance as the PRP group, except for the absence of platelet therapy components.Neither the patient nor the operator can identify the specific component,All the blood components on the blood bag shall be covered with black after examination by therapists, nurses and blood transfusion medical personnel, who will not participate in PRP operation.Researchers randomly grouped patients by SPSS software. PRP operators only checked and operated with patients' general information and recorded the injection volume without knowing the blood composition and grouping.The efficacy is evaluated by a third person who do not know the grouping status;In the data summary stage, all data are analyzed by a third party to separate researchers and statisticians.

Interventions

Control group

The control group is plasma placebo group, and patients can receive a set of knee meniscus rehabilitation treatment plan in the 2018 edition of the American Physical Therapy Association's "Joint Pain and Movement Disorders due to meniscus and knee cartilage Injury" clinical practice guidelines [16],and appropriate rehabilitation guidance.At the same time, different doses of subgroups of knee joint cavity puncture plasma injection operation.

Experimental group

The experimental group is PRP treatment group. In addition to the above rehabilitation treatment plan and guidance, knee joint puncture injection PRP treatment is performed for subgroups with different doses [3].

Withdrawal from trial

Patients will be withdrawn for either of the following:

Those cases that do not meet the inclusion criteria and are mistakenly included should be eliminated;
Those who do not affect data collection and safety evaluation according to the requirements should be excluded;
Subjects with poor compliance and self-withdrawal;
Cases that are discontinued due to serious adverse events that make continuation of the trial unsuitable.

Outcome measures

Primary outcome

Lysholm score scale is used to evaluate the changes of knee function.At the same time, magnetic resonance imaging (including T2mapping technology) is used for quantitative analysis. T2 relaxation time is measured by magnetic resonance T2mapping imaging technology. The water content, composition and anisotropy changes of collagen fibers in meniscus are noninvasive detected at the molecular level to evaluate the physiological and pathological status of meniscus. Quantitative analysis of meniscus damage and repair healing state in early stage.

The scale is assessed by an unwitting third person,and the MRI is diagnosed by a radiologist.

Secondary outcome

Visual analogue scale (VAS) and infrared thermal imaging [17] are used to evaluate the changes of patients' pain, and quality of life score (36-item Short Form Health Survey) is used to evaluate patients' quality of life. The musculoskeletal ultrasonography is used for semi-quantitative evaluation of meniscus injury morphology and signal.

In the meantime,the incidence of adverse events and compliance evaluation indexes are set for safety evaluation.

Data collection

Lysholm scale and VAS score are followed up before treatment, 1 week, 3 weeks, 5 weeks and 1 month, 3 months, 6 months after treatment. SF-36, musculoskeletal ultrasound, MRI (including T2mapping), and infrared thermal imaging are followed up before and 3 and 6 months after treatment.Table 2 lists the planned data collection at each point in time.

Table 2 Scheduled events and timeline of trial

stage	Be selected	Treatment period & Follow-up period
Point in time	pre-treatment	First week of treatment	Third week of treatment	Fifth week of treatment	The first month after treatment	Three months after treatment	Six months after treatment
Basic medical history	√
Sign informed consent	√
Determine inclusion and exclusion criteria	√
Fill in the basic information	√
Compliance record		√	√	√	√	√	√
Observation outcomes
VAS	√	√	√	√	√	√	√
Lysholm score scale	√	√	√	√	√	√	√
SF-36	√					√	√
Musculoskeletal ultrasound	√					√	√
MRI(including T2mapping technology)	√					√	√
Infrared thermal imaging	√					√	√
Safety observation
Record adverse events		√	√	√	√	√	√
Other work
Compliance evaluation		√	√	√	√	√	√

In addition, it is also necessary to collect the patient's general condition, past history, personal history, family history and other relevant information. Include name, sex, age, height (cm), weight (kg), phone number, previous trauma history, smoking and drinking history, drug and food allergy history, and medication history for other diseases.

Sample size calculation

This study is a randomized controlled trial, using the multi-group differential analysis method, according to the literature review, the treatment rate is expected to be 70% in the low-dose group, 80% in the medium-dose group, 90% in the high-dose group, and no treatment effect in the control group.Bilateral α=0.05 was set with 90% certainty. Take the following formula to calculate each group of 18 people, a total of 72 people.

After fully considering the possible culling and shedding in this research, the loss of follow-up rate is considered to be about 10%.Therefore, 84 patients are studied.

Data management

Ensure data collection, input, summary and update through a wide range of applications, etc. The research data of the scale will be collected by online APP and updated by spreadsheet summary. The integrity, consistency and rationality of the data will be reviewed regularly. Objective examination can be recorded truthfully in the case report form.

Quality control

In order to facilitate the smooth progress of this project, the relevant operating procedures of clinical trials and implementation process shall be scientifically, rigorously and standardizing;
Unified training should be conducted for researchers to be familiar with the implementation plan of diagnosis and treatment measures, so as to improve the consistency of internal observation and inter-observer consistency of researchers and ensure the reliability of clinical trial conclusions;
Strictly record the relevant evaluation indexes of the corresponding treatment nodes of patients, eliminate the reasons for shedding and the reasons for the termination of the experiment, etc;
Set up a quality monitor to conduct quality control and supervision over the whole process of the study, check and confirm the correctness and completeness of all the records and reports of the study data as well as the filling of the case report form, and ensure the consistency with the original data;
To ensure the smooth progress of the research, a detailed research plan, progress arrangement and assessment indicators should be formulated, and specific provisions should be made on the division of labor and organization and coordination of each group;
In order to ensure patient compliance, techniques and drugs associated with the study therapy cannot be used during the trial period.

Statistical method

SPSS23.0 statistical software (SPSS, USA) is used for processing. For the clinical data of the experimental group and the control group, independent T test is used for the comparison of continuous variables between the two groups, analysis of variance is used for the three groups and above, and Chi-square test or Fisher exact test is used for counting data. P≤0.05 indicated statistical significance.

At present, it has become a consensus that meniscus repair or meniscus regeneration in the treatment of meniscus injury may prevent or delay the occurrence of osteoarthritis [18].However, improving regeneration and improving healing rates after injury have been major challenges.Although PRP treatment has been confirmed to have a positive effect on tissue healing [19-20], limited to different therapeutic doses of PRP, different preparations of PRP treatment, different courses of PRP treatment and other heterogeneous reasons, PRP treatment of meniscus injury is still controversial to some extent.

Based on the above situation, this study intends to start to study dose difference comparison through several commonly used therapeutic doses of PRP.Based on previous literature and clinical experience, it is known that the selection of several commonly used doses can maximize the safety of patient treatment in the trial. Meanwhile, the treatment of these several commonly used doses is also effective, ensuring the effectiveness of patient treatment.On this premise,we will try to find the clinically appropriate dose of PRP for meniscus injury through comparative study of several commonly used doses, so as to provide some reference for the formulation of clinical guidelines for the treatment of meniscus injury with PRP.

In this study, young people aged 18 to 44 years old are considered for the selection of subjects, because at present, the nature of this research center decides to collect young patients with training injuries from a rich source, and free diagnosis and treatment, and patient compliance is good;and most of the patients are unit personnel, and the sample loss rate is smaller than that of social personnel, which is convenient for follow-up.The reason for the selection of meniscus injury of degree Ⅰ and Ⅱ lies in the basic principle of conservative treatment, while most meniscus injury of degree Ⅲ is mainly surgical treatment. In order to reduce interference factors, I and II degree meniscus injury are selected.

The design advantage of this study is that it fully considers the importance of blinding.Blood components of the experimental group and the control group are consistent in color and appearance, which is different from the control design of previous studies. In the previous PRP treatment group, sodium hyaluronate and other drugs were mostly used, which may lead to patients subjectively believing that there are differences between the two treatments, and there may also be obvious deviation in the efficacy evaluation;of course, in order to ensure medical safety, it is essential to check the blood composition and other important information. This work is checked by therapists, nursing staff and blood transfusion personnel. The test subjects cover the blood composition on the blood bag with full black, without involving the PRP treatment operator.In order to ensure the objectivity of the efficacy evaluation, we select therapists with rich clinical experience who do not know the group status to evaluate, so as to avoid subjective factors affecting the evaluation results.Simultaneously,all data are analyzed statistically by a third party to separate researchers and statisticians. This blinding method minimizes the deviation of the experiment and ensures the relative objectivity of the experiment.

Without doubt, there are still some limitations in the design of this study.For example, although the patients we select are of the same age and had roughly the same body size, it do not mean that the joint cavity capacity of all patients is similar, which may still exist individual differences.If conditions permit, 3D printing technology, MRI special imaging technology and other aspects can be considered to measure the capacity of the joint cavity, which is conducive to the precise selection of therapeutic dose.For another example, several commonly used therapeutic doses of PRP may lead to deviation of comparative data due to the different degree of meniscus injury. If necessary, we need to further increase the sample size or (and) further group the degree of meniscus injury for a detailed study.In addition, due to the different treatment intentions of patients, part of the subjective evaluation content may be affected, so we need to design six follow-up time points for a more objective observation of the efficacy.

In conclusion, this study is a practical clinical study. Before this study is carried out, we find that there is a large difference in the dosage of PRP for meniscus injury selected by different doctors in clinical practice, which prompt us to conduct a comparative study on the therapeutic dosage of PRP for meniscus, which is conducive to the standard of clinical application of PRP treatment and further mining the basic theory of PRP treatment. After the analysis of the test results, further studies on the dose-effect relationship may be considered, or studies on precise dose injection therapy may be carried out through 3D printing technology.

Trial status

The trial is ongoing with active recruitment, which began in January 2022.The expected enrollment rate is 4 to 6 patients per month, with an estimated enrollment period of 12 to 24 months.

PRP:Platelet-rich plasma VAS:Visual analog rating scale SF-36:36-item Short Form Health Survey

Acknowledgements

Thanks to Dr. Wang Wenchun (Department of Rehabilitation Medicine, General Hospital of Western Theater Command) for providing consultation, revision and methodological guidance.

Authors’contributions

CC is the investigator of the study and conceived the clinical study;WW and JCL revise the study design and protocol;WW directs statistical analysis and is responsible for data management;RP, XM and others recruit patients;CC, ZW, ZX, JZ,XZ, JYL, LW and others are grouped to be responsible for operation, evaluation.XG,LB and XH are responsible for blood bag inspection and exercise instruction.All authors read and contribute intellectually important material and approved the final manuscript.

Funding

This study was Supported by Key R&D Projects of Sichuan Science and Technology Plan (No.2020YFS0168).

Availability of data and materials

The datasets use and/or analyze during the current study are available from the corresponding author or first author on reasonable request.

Ethics approval and consent to participate

The Institutional Review Committee of the General Hospital of Western Theater Command has approved the trial (Ethics number: 2022EC1-008).Any significant changes in eligibility criteria, interventions, results or analysis of the research programme will be undertaken under the supervision and approval of the Institutional Review Board. Written informed consent will be collected from each participant as required by the Ethics Committee and in accordance with the Declaration of Helsinki.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Author details

^*Correspondence: [email protected]

¹Department of Rehabilitation Medicine, General Hospital of Western Theater Command, Chengdu,China

²College of Health Care, Chengdu University of Traditional Chinese Medicine,Chengdu,China

³School of Medicine, Southwest Jiaotong University,Chengdu,China

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No competing interests reported.

A comparative study of the efficacy of different doses of platelet-rich plasma in the treatment of Degree I and Degree II knee meniscus injury in young adults: Study protocol for a prospective, single-center, three-blind, randomized controlled trial

Status:

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Abstract

Figures

Background

Trial objectives

Methods/design

Discussion

Abbreviations

Declarations

References

Additional Declarations

Status:

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