Clinical trial NCT05014542: Needling Techniques for Knee Osteoarthritis
Official title: Needling Techniques for Tonifying Kidneys and Dredging Meridians for Knee Osteoarthritis: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Knee Osteoarthritis
Kidney Yin Deficiency
Kidney Yang Deficiency
Keywords: Needling
Techniques
Randomized
Reinforcing
Reducing
Acupuncture
Lead sponsor: Family Medicine Practice Svijetlana Perculija Durdevic, MD
Sponsor class: OTHER
Collaborators: name: Nanjing University of Chinese Medicine, Xueping Zhou, Li Ren
name: School of Medicine, University of Zagreb, Pero Hrabac
name: Health Center Zagreb East, Ljiljana Karadakic
First posted: 2021-08-20
Enrollment: 64
Sex: ALL
Minimum age (years): 50
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: A randomized, controlled, open-label, interventional, prospective.
Primary purpose: TREATMENT

Brief summary: The purpose of this open-label, thirty-nine weeks-long clinical study is to investigate the efficacy of acupuncture for Knee Osteoarthritis (KOA) as adjunctive therapy to conventional treatment in comparison to conventional therapy alone and assessment of its eventual prolonged effectiveness after nine and twenty-four weeks without treatment. The long-term effects of acupuncture on KOA are not yet confirmed. A safety assessment will be done.

It will be interesting to find possible additional benefits of acupuncture while treating knee/s with an advance determined acupuncture protocol for KOA and Kidney Deficiency Syndrome (KDS) since Traditional Chinese Medicine (TCM) theory connects KOA with KDS. Acupuncture treatment point prescription will use local points for KOA and non-local points with their influence on KOA through Kidney deficiency as a root cause.

The deep layered chronic pathological condition like KOA requires a higher number of acupuncture treatments. This study will provide three cycles of acupuncture treatments to participants of the Acupuncture (A) group, which are three weeks long each, with treatment frequency three times weekly. It is expected that the study design with twenty-seven acupuncture treatments of KOA in fifteen weeks achieves improvement with the KOA and Kidney Deficiency Syndrome (KDS), additionally. Also, treatment effectiveness on KOA and KDS is expected to persist at the final assessment nine weeks after the last acupuncture treatment. That could confirm the holistic aspect of TCM.

Sixty-four patients with symptomatic KOA will be randomly allocated into the A group or C group (standard care) according to their permanent, unique, and coincidental Personal Identification Number which is randomly given to all citizens in Croatia. Before the experiment starts participant's demographic and disease parameters of both groups will be compared at baseline. Prescribed acupuncture protocol will be provided firstly to the Acupuncture group. Objective assessments of therapeutic efficacy will be done by a physiatrist at three time-points: baseline, after final acupuncture treatment (15th Week), and at the 24th Week. Subjective evaluation of symptoms intensity, by participants, will be assessed by Western Ontario and McMaster University Arthritis Index (WOMAC) total score and subscales, Visual Analogue Scale (VAS), and Kidney Deficiency Syndrome Questionnaire (KDSQ) every three weeks till the 24th week (nine assessments with baseline one). Analgesics taken by participants in the last three days before every assessment will be recorded.

Participants from the study were promised to receive equal acupuncture treatment after completion of the experiment and belonging assessments if they were randomised into the non-acupuncture group (Control). So, the participants of the C group cross over and after the 24th week of this study start with the identical acupuncture treatment protocol.

This study added later the 10th identical assessment to both groups of participants to estimate the within-subject C group effect of the acupuncture treatment protocol and to estimate the duration of treatment effect in the A group 24 weeks after the last acupuncture treatment.

Also, in the 24th week was added the Lequesne index, as a more objective and clearer measure of symptomatic and functional improvement of the knees. Participants were asked to fill out the questionnaire according to the actual condition and according to a memory of "how it was before the experiment start".

Hypothesis: A decrease in symptom intensity could be achieved after treatment in the experimental group compared to the control.

Detailed description: The prevalence of KOA in practice is high and patients are well motivated for additional treatment regarding their pain and functional impairment. Symptoms of KOA are mainly pain in the knees and stiffness. Other manifestations of KOA include sequelae such as muscle weakness, poor balance, and joint distortion. KOA occurs in middle and old age. Pain is worse with joint usage and relieved by rest. Limitation of motion mainly results from osteophytes and synovial hyperplasia. Bony swelling reflects remodelling of the bones, cartilages, and synovial thickening. Joint deformity is a sign of advanced joint damage and squaring, subluxation could happen. Instability may be a sign of weakness of the muscle and joint instability.

The prototype of a patient with KOA is an older patient with pain and disturbed function in one or in both knees, with possible less pronounced symptoms like weakness, insomnia, depression, tinnitus, forgetfulness, feeling cold, hot, low back pain, thirst at night, urogenital symptoms related to deeply layered disorders (Kidney deficiency symptoms). By treating both causes simultaneously it is to be expected a reduction of the reactive symptoms is the main effect, but also patient could experience changes in the presentation of its root symptoms. The treatment effect could present better function of the knee and could induce a patient's better quality of life through influence on Kidney deficiency.

The acupuncture treatment strategy for KOA logically follows the TCM syndrome differentiation and understanding of its pathogenesis. In KOA, the treatment principle distinguishes the root as deficient and the branch as an excess condition. Weak root (Kidney and Blood deficiency) condition contributes to the formation of branch syndrome (bone Bi syndrome). Aspiration with treatment would be to tonify the Kidney and Blood, nourish Qi, expel evils, remove dampness, promote blood circulation, and remove the obstruction from the channels and collaterals.

The study design It is expected to confirm the therapeutical efficacy of acupuncture in the A group where acupuncture treatment is adjunctive to conventional as opposed to the C group which receives only conventional treatment (analgesics).

Recruitment of participants was done from the target population: patients in two Family Medicine practices with confirmed and symptomatic KOA. The study population was formed with: inclusion criteria - patient 50 years old or above with KOA for at least 6 months, painful knee in last month, radiographic changes of OA (Kellgren-Lawrence grade 2 or more) and signed informed consent, and exclusion criteria - if an intra-articular injection into knee within 3 months preceding entry of participant into study, severe chronic or uncontrolled concomitant disease, bleeding diathesis, or anticoagulant use.

Mostly all 64 patients will be recruited from Family practices. All medical data of participants are available to the investigator. After previously fulfilling the SOAP (Subjective, Objective, Assessment, Plan) form and after getting informed written consent from all, the study population will be randomly allocated into two groups according to order by size of their permanent, unique eleven numbers long Personal Identification Number (OIB), which is given to all citizens in Croatia by birth. Its first ten numbers are accidentally chosen digits and a last digit is a control number. Every second participant in the accidental order by size of OIB will belong to the same group. Odd ones will belong to the A and even numbers to the C group. Demographic and disease parameters will be compared between the two groups at baseline. All patients in the A and C groups will receive analgesics, which dosages could be modified according to the participant's needs. Analgesics include nonsteroidal anti-inflammatory drugs (NSAIDs) and/or tramadol in both trial groups. Taken doses of analgesics in both groups will be recorded at Weeks 0, 3, 6, 9, 12, 15, 18, 21, and 24 and the dose represents an average daily dose of analgesics in the last three days according to the statement of participants. The recorded dosage will be shown as the comparable dose of the selected representative, which will be ibuprofen as the most prescribed one. Given data will be statistically processed and analyzed.

Patients in the A group will start with acupuncture treatment in September 2021 with the first of three planned treatment cycles. Each of the three treatment cycles will be three weeks long, one therapeutic cycle consists of 9 treatments each, and each two acupuncture cycles will be separated by three weeks period without treatment. Patients will receive acupuncture treatments three times per week.

Acupuncture treatment protocol: local treatment points Dubi (ST-35), Neixiyan (EX-LE-4) and Heding (EX-LE-2), Xuehai (SP-10), Yanglingquan (GB-34), Yinlingquan (SP-9), Zusanli (ST-36), Sanyinjiao (SP-6), and points selection based on kidney deficiency syndrome Taixi (KI-3), Guanyuan (CV 4), and Shenshu (BL-23).

A disposable sterile acupuncture needle 0.30 × 40 mm will be used. The depth and angle procedure predict straight needling and 1-1.5 inches deep, with a mild reinforcing-reducing method for local points, further straight and 0.5-1 inch deep, reinforcing method for points based on KDS. The time of needling will be 30 minutes, and the time point of reinforcing and reducing manipulation will be every 10 minutes, three times in total.

Sample size The sample size was calculated based on the study published by Berman et al.,1999. The authors used a shorter treatment period than the one envisioned for the present study (8 vs. 15 weeks). For sample size calculation, the following data from the mentioned study were used: WOMAC total score in A and C study groups was comparable at the baseline. After 8 weeks of treatment, WOMAC total scores were in group A 28,08 (SD = 17,96), in group C 50,11 (SD = 14,52).

The sample size was calculated using the PASS software package, with envisioning a two-sided test with unequal variances: type I error 0,05, power 0,95. Group sample sizes of 16 and 16 (i.e. complete study population of 32 subjects) achieve 95,78% power to reject the null hypothesis of equal means when the population means difference is μ1 - μ2 = 28,1 - 50,1 = -22,0 with standard deviations of 18,0 for A group and 14,5 for C group, and with a significance level (alpha) of 0,050 using a two-sided two-sample unequal-variance t-test.

In this study, the treatment period will be significantly longer compared to the study used for the calculation and it is expected a certain proportion of subjects to drop off the study and be lost to follow-up, the study population will be doubled to a total of 64 subjects.

Research methods The clinical question "Could the prolonged design of acupuncture treatments on patients with knee osteoarthritis (KOA) decrease pain and improve the function of the knee joints, and additionally achieve positive effects on the debilitating symptoms of a Kidney deficiency as a root cause of KOA, measured by recognized questionaries?" arise. The outcomes that matter the most are determined under clinical questions.

Evaluation of the therapeutic effect of acupuncture on KOA will include renowned WOMAC, VAS, and KDSQ scores, drug dosages are taken at Weeks 0, 3, 6, 9, 12, 15, 18, 21, and 24. WOMAC is a renowned questionnaire used by health professionals to evaluate the condition of patients with KOA. It measures 5 items for pain, 2 for stiffness, and 17 for functional limitation. VAS continuous scale of 100 mm in length is a widely used and recognized scale for pain intense assessment. The KDSQ questionnaire is a valid and reliable measure for the evaluation of the Kidney Yin and Yang deficiency syndromes in Hong Kong Chinese middle-aged women, constructed by Chen et al., 2012. KDSQ represents a valid questionnaire for the assessment of Kidney deficiency in this study population.

Participants from the study were promised to receive equal acupuncture treatment after completion of the experiment and belonging assessments if they were randomised into the non-acupuncture group (Control). So, the participants of the C group cross over and after the 24th week of this study start with the identical acupuncture treatment protocol.

This study added later the 10th identical assessment to both groups of participants to estimate the within-subject C group effect of the acupuncture treatment protocol and to estimate the duration of treatment effect in the A group 24 weeks after the last acupuncture treatment.

Also, in the 24th week was added the Lequesne index, as a more objective and clearer measure of symptomatic and functional improvement of the knees. Participants were asked to fill out the questionnaire according to the actual condition and according to a memory of "how it was before the experiment start".

Data will be stored electronically on a database with secured and restricted access. Data transfer will be encrypted and any information capable of identifying individuals removed.

Study analysis. This study tends to evaluate the effect of acupuncture treatment in WOMAC total score at the end of the acupuncture treatment protocol (15th Week) as a primary outcome measure. The persistence of the treatment effect will be assessed on the 24th Week (nine weeks after the last treatment). Secondary outcome measures will be WOMAC subscales, VAS, and KDSQ scores, drug dosage taken according to the statement of participants, physiatrist's measures, and Lequesne index. Baseline data will be obtained before the start of acupuncture treatments. Endpoint measures at specified time periods will be calculated from outcome measures in comparison to data at the baseline point. The effect size will be calculated in the comparison between data in the A group and data in the C group. Efficacy should be determined for primary and secondary outcomes, respectively. The primary efficacy analysis will be based on the intention to treat analysis set, defined as all randomized subjects included in the statistical analysis and analyzed according to the group were originally allocated, regardless of if they received the treatment. Statistical comparisons for total and subscale scores based on the WOMAC will be made using a repeated-measure model with terms of values for measuring at Weeks 3, 6, 9, 12, 15, 18, 21, and 24, and baseline as a covariate. The treatment difference and its 95% confidence interval will be estimated from this model. The same approach will be used for analyzing the VAS score and KDSQ questionnaire. All statistical tests will be two-sided.

The physiatrist's assessment, in three time-points (baseline, 15th Week, and 24th Week) should be used as a controlled measure. It'll include standard physiatrist KOA measurements (knee and thigh circumference, range of motion of knee).

A participant will be considered to have withdrawn from the trial when consent is revoked or if the participant cannot be contacted or located. Participants will not be withdrawn from the trial for protocol violations. Withdrawal due to an adverse event should be distinguished from withdrawal due to insufficient response.

All adverse events will be recorded in the Adverse Event Report Form at every treatment. If happen adverse event will be followed until the resolution of the event occurs. The serious adverse event must be reported to Medical Ethical Committee.

Expected endpoints Is to be expected pain relief and increased joint movement. Secondly, it could be expected to diminish symptoms of Kidney deficiency, reduction of analgesics dosages, confirmation of acupuncture safety as a secondary outcome which should be considered supportive. WOMAC could be reduced by 20 and KDSQ by 15. KOA pain and drug dose taken could be reduced by half.

Lowering the intensity of symptoms of Kidney deficiency represents an additional value that can influent the life quality of patients.

Research adjectives This is a prospective, interventional, randomized, open-label, controlled trial. It is supported by recent scholarly, peer-reviewed literature. The research method reflects the approach needed to answer the research questions. Research is addressing a gap in the literature that would contribute new findings. The research topic is based on a tangible and cited problem. The research will be conducted with data collection and analysis, any deviations will be documented and approved by the study performer. The study is originally designed. The acupuncture treatment plan for KOA is obtained with the assistance of Professor Xueping Zhou. The tendency of study is to be relevant and made under high standards applied in research in medical fields.

Conditions for completing the project The study will be conducted in a Family Medicine practice which is led by the study performer. All financial and operating burdens will be funded from practice resources.

Eligibility criteria: Inclusion Criteria:

* Clinical diagnosis of Knee Osteoarthritis
* Knee Osteoarthritis for at least 6 months
* painful knee in last month
* radiographic changes of the knee (Kellgren-Lawrence grade 2 or more)
* signed informed consent
* participant can move independently

Exclusion Criteria:

* if the participant got knee intra-articular injection 3 months before his entry into the study
* uncontrolled malignant disease
* unstable heart disease
* advanced organ failure disease (NYHA III or IV, or a more than the twofold increase of creatinin, or marked dyspnea)
* unstable psychiatrist's disease
* bleeding diathesis
* anticoagulant use

Primary outcomes:
measure: WOMAC score at treatment completion time points
timeFrame: 15th Week
Secondary outcomes:
measure: VAS value at last assessment time point
timeFrame: 24th Week
measure: VAS value at complete acupuncture treatments time point
timeFrame: 15th Week
measure: VAS at the end of study-24 week after last treatment (A group), after last treatment (C group)
timeFrame: 39th Week
measure: KDSQ score at last assessment time point
timeFrame: 24th Week
measure: KDSQ score at completed acupuncture treatments time point
timeFrame: 15th Week
measure: KDSQ at the end of study-24 week after last treatment (A group), after last treatment (C group)
timeFrame: 39th Week
measure: Drug dose taken by a participant at last assessment time point
timeFrame: 24th Week
measure: Drug dose taken by a participant at completed acupuncture treatments time point
timeFrame: 15th Week
measure: Drug dose taken by a participant at the end of study- 24 week after last treatment (A group), after last treatment (C group)
timeFrame: 39th Week
measure: Knee active extension at last assessment time point
timeFrame: 24th Week
measure: Knee active extension at completed acupuncture treatments time point
timeFrame: 15th Week
measure: Thigh circumference 15 centimetres above patellar superior margin at last assessment time point
timeFrame: 24th Week
measure: Thigh circumference 15 centimetres above patellar superior margin at completed acupuncture treatments time point
timeFrame: 15th Week
measure: WOMAC score at last treatment time point
timeFrame: 24th Week
measure: WOMAC at the end of study- 24 week after last treatment (A group), after last treatment (C group)
timeFrame: 39th Week
measure: Knee active flexion at last assessment time point
timeFrame: 24th Week
measure: Knee active flexion at completed acupuncture treatments time point
timeFrame: 15th Week
measure: Knee circumference over the middle of the patella in the knee extended position at last assessment time point
timeFrame: 24th Week
measure: Knee circumference over the middle of the patella in the knee extended position at completed acupuncture treatments time point
timeFrame: 15th Week
measure: Lequesne index at Week 24th effect size between A and C group participants
timeFrame: 24th Week
Other outcomes:
Locations:
city: Zagreb
country: Croatia
facility: Family Medicine Practice Svijetlana Perculija Durdevic, MD
Study officials:
affiliation: Family Medicine Practice Svijetlana Perculija Durdevic, MD
name: Svijetlana Perculija Durdevic, M.D.
role: PRINCIPAL_INVESTIGATOR
References: