The efficacy and safety of the Shaoyao Shujin tablet for knee osteoarthritis: study protocol for a randomized controlled trial

Study design

This is a multicenter randomized, double-blind, placebo-controlled trial. General
ethical approval was issued by the Ethics Committee of Guangdong Provincial Hospital
of Chinese Medicine (No. A2015-01-2-1), and participating center ethical approval
was issued by the Clinical Trial Ethics Committee of Huazhong University of Science
and Technology (No. FZ-1302-01), the Ethics Committee of The First Affiliated Hospital
of Anhui University of TCM (No. 2015AH-03), the Clinical Trial Ethics Committee of
The First Affiliated Hospital of Hunan University of TCM (No. 2015-YW-001), and the
Ethics Committee of Shanghai Hospital of TCM (No. 2015SHL-05). Subjects will be enrolled
at these five hospitals. The trial protocol has been registered in the Chinese Clinical
Trial Registry (ChiCTR-IPR-15006194). All study participants will sign the written
informed consent before participation. The trial is financially supported by Shanghai
Fosun Pharmaceutical Development Co., Ltd, Shanghai, China, which will participate
in the study design, but will not be involved in data collection, data management,
analysis, interpretation of data or the decision to submit the report for publication,
but will provide all test drugs.

Recruitment and consent

A target sample size of 276 KOA patients, who are regularly followed up at outpatient
clinics of the Department of Orthopedic Surgery in each participating center, will
be recruited. All candidates will go through a standardized interview process and
receive more information about the study and the treatments. The purpose, procedures,
and potential risks and benefits of the study will also be explained thoroughly to
the participants. The more painful knee will be chosen as the study knee, and if both
knees have the same symptoms, we will choose the right side. The participants will
be able to withdraw from the study at any time without consequence. The trial will
be executed from February 2015 to February 2016 including enrollment and follow-up
(see Fig. 1).

Fig. 1. Study flow-chart

Inclusion criteria

Participants meeting the following criteria will be included:

Meet the diagnostic criteria for KOA (American College of Rheumatology criteria 10])

Aged from 40 to 70 years old

Symptomatic KOA with pain of at least 30 mm on a 100-mm visual analog scale (VAS)

Grade 0–3 on the Kellgren-Lawrence grading system

No serious medical history

No known drug allergies

Willingness to give written informed consent and willingness to participate in, and
comply with, the study

Exclusion criteria

Participants meeting one or more of the following criteria will be excluded:

Grade 4 on the Kellgren-Lawrence grading system

Medication history for KOA within 1 week, such as NSAIDs, steroids, glucosamine,
chondroitin sulfate, sodium hyaluronate, etc.

Allergy to study drug

Non-degenerative osteoarthritis, such as rheumatoid arthritis, gouty arthritis, infectious
arthritis, Charcot arthritis, etc.

Unwilling to give informed consent

Interventions

Eligible patients will be randomized into the three groups: (1) the high-dose SST
group (HD group), (2) the low-dose SST group (LD group), and (3) the placebo tablet
group (control group). The SST will be provided by the Shanghai Fosun Pharmaceutical
(Group) Co., Ltd, Shanghai, China (drug permit license number 2014L00464) and weighs
0.35 g per tablet. The components of the SST are Radix paeoniae alba, Radix Gentianae Macrophyllae, oyster, licorice, scorpion, and centipede. The placebo tablet will be manufactured
identical to the SST in terms of color and odor by the same manufacturer. In the HD
group four SSTs will be administered three times per day for 6 weeks, while in the
LD group two SSTs and two placebo tablets, and in the control group four placebo tablets
at the same frequency and for the same duration. Patient visits will be performed
at baseline and 2, 4, 6 and 10 weeks after treatment. Assessments including the Western
Ontario and McMaster Universities Index (WOMAC) score and the VAS score will be recorded
on the relevant knee during all visits.

As a short-term study aims to explore the efficacy and safety of SST for the symptomatic
management of KOA, we think that 6 weeks’ treatment and 4 weeks’ follow-up will be
enough to observe whether there are differences between the HD group, the LD group
and the placebo tablet group.

During the process, when patients experience moderate pain or a VAS score over 40
mm, ibuprofen sustained-release capsules will be administrated as rescue medication.
Rescue medication consumption and time will be recorded in each randomized group when
the subjects use rescue medication. The patients will not be allowed to use other
drugs aiming to treat KOA.

Outcome measures

Primary outcome measure

The primary efficacy endpoint of the study will be the WOMAC score 11]. The WOMAC score is a widely used proprietary set of standardized questionnaires
used by health professionals to evaluate the condition of patients with osteoarthritis
of the knee and hip, including pain, stiffness, and physical functioning of the joints.
The index measures five items for pain (score range 0 to 20), two for stiffness (score
range 0 to 8), and 17 for physical function (score range 0 to 68). It will be measured
during all the assessment visits (baseline, 2-, 4-, 6- and 10-week follow-up).

Secondary outcome measure

The secondary efficacy endpoint of the study will be the VAS score, which is a pain
score ranging from 0 mm (no pain) to 100 mm (worst pain ever experienced) 12], measured during all the assessment visits (baseline, 2-, 4-, 6- and 10-week follow-up).
The VAS score is usually a horizontal line, 100 mm in length, anchored by word descriptors
at each end. Patients mark the point of their current pain on the line. The VAS score
is then determined by measuring in millimeters from the left end of the line to the
point that the patient marked.

Safety assessments

All subjects will be questioned about adverse events during the treatment at each
visit, and all adverse events reported will be analyzed, regardless of the investigators’
assessments of causality. Safety will be assessed by the following tests on all subjects:
physical examination (temperature, respiration, heart rate, blood pressure, height
and weight), complete blood cell count, urinalysis, stool examination, fecal occult
blood test, liver function (alanine aminotransferase (ALT), aspartate aminotransferase
(AST), alkaline phosphatase (ALP), serum total bilirubin (STB), and ?-glutamyl transpeptidase
(?-GT)), renal function (creatinine (Cr), micro-albuminuria, serum cystatin C, and
urinary N-acetyl-?-glucosaminidase) and an electrocardiogram (ECG) at baseline and at 2- and
6-week visits.

Randomization and blinding

Patients who meet the inclusion criteria will be randomly assigned to one of three
groups (HD group, LD group, control group) in a ratio of 1:1:1 using a computer-generated
random allocation sequence through the stratified block randomization method of SAS
version 9.1.3 (SAS Institute Inc., Cary, NC, USA). Each patient will receive a unique
randomized test number corresponding to the specified drug, according to the group
allocation. An emergency envelope has been prepared for each test number and is to
be opened.

The trial will be blinded to both patients and treating physicians. For test drug
blinding, the placebo tablet will be manufactured identical to the SST in terms of
color and odor. The drugs are administered by an independent clinical assistant in
each center who takes responsibility for the drugs’ distribution, storage and return.
Any members who have access to the drug will not participate in case observations
or efficacy evaluations. Before the trial two different bottles will be prepared:
bottle A contains a 2-week dose of SSTs and bottle B contains a 2-week dose of placebo
tablets. Bottles A and B will be packaged with the same label for patient and assessor
blinding. For the HD group, two A bottles will be assigned; for the LD group, one
A bottle and one B bottle will be assigned; and for the control group, two B bottles
will be assigned. During baseline, and 2-, and 4-week visits, patients will be assigned
two bottles according to their group, and 14 rescue medications. They will then be
instructed to take two tablets from each bottle every time they take their drugs.
At the next visit, the patient should return all the rescue medications they didn’t
taken.

Sample size

Calculation of sample size is based on a similar herbal drug study assessing the short-term
efficacy of two types of Traditional Chinese herbal patches, Fufang Nanxing Zhitong Gao and Shangshi Jietong Gao13]. We estimate that an absolute improvement of 10 in the WOMAC total score is likely
to be the smallest clinically relevant difference for patients with KOA. We assume
that the standard deviation of the total WOMAC score to be 18.2 at baseline. Based
on these assumptions, we will require 79 patients in each group to have at least an
80 % power (??=?0.8) and to rule out a two-sided type I error of 5 % (??=?0.05). The number of patients actually provides less than 80 % power, assuming
a withdrawal rate of 15 %. Therefore, we will recruit a total of 276 patients, 92
patients in each group.

Statistical analysis

The data will be collected and analyzed according to the intention-to-treat principle.
An analysis of variance (ANOVA) or chi-square test will be used to compare baselines
among patients. Efficacy analyses will be performed for both the intent-to-treat (ITT)
population and the per-protocol (PP) population. The ITT population will consist of
all randomized subjects who have been administered at least one treatment. In a PP
analysis, only patients who complete the entire clinical trial according to the protocol
are counted towards the final results. Primary outcome will be compared among groups;
the extent and time pattern of rescue medication use in each randomized group will
be reported: in considering comparison of the underlying outcomes of rescue medication
use, we will assume the use varies with time and, to allow for dependence within patients,
we will adopt a multilevel regression approach with rescue as a time-dependent covariate
14]. All statistical analyses will be performed using SAS 9.2 software. All statistical
tests will be two-sided, and the level of significance will be set at 0.05.