Safety and Efficacy of Weishen Decoction in Elderly Patients with Osteoporosis and Kidney-Yang Deficiency: A Randomized Trial

Summary

This double-blind, placebo-controlled trial evaluated 12 weeks of Weishen Decoction monotherapy in 72 older adults with osteoporosis and kidney-yang deficiency. Outcomes included traditional Chinese medicine syndrome response, low back pain, bone mineral density, bone turnover markers, and safety. Findings provide preliminary support for further larger, longer-term confirmatory clinical trials.

Abstract

This study described the protocol and evaluated the safety and preliminary efficacy of Weishen Decoction monotherapy. This randomized, double-blind, placebo-controlled trial enrolled 72 eligible patients (aged 60–80 years) who were assigned 1:1 to receive either Weishen Decoction granules or placebo for 12 weeks. No background conventional osteoporosis medications (including calcium or vitamin D) were permitted. The primary outcome was the total effective rate based on the traditional Chinese medicine TCM syndrome score reduction (≥30% reduction using the back pain visual analog scale (VAS), bone mineral density (BMD) at lumbar spine and femoral neck, and serum bone metabolism markers (procollagen type I N‑terminal propeptide (PINP), C‑terminal telopeptide of type I collagen (β-CTX), osteocalcin (OC)). Safety was assessed via laboratory tests and adverse event monitoring. All 72 patients completed the trial. The protocol-defined primary outcome showed a higher total effective rate with Weishen Decoction compared with placebo (66.7% vs. 41.7%; P < 0.05). Exploratory BMD findings suggested a between-group difference in femoral neck BMD change (P < 0.05), whereas lumbar spine BMD changes did not differ significantly. Given the 12‑week treatment duration, these BMD results are preliminary and hypothesis‑generating. No serious adverse events occurred in either group. These trial results demonstrate that a 12‑week course of Weishen Decoction monotherapy is feasible and safe in this population. The observed improvements in TCM symptoms and pain, along with suggestive changes in femoral neck BMD, warrant further long‑term confirmatory trials.

Introduction

Osteoporosis is a systemic skeletal disease characterized by reduced bone mass, deterioration of bone microarchitecture, and increased bone fragility. Osteoporotic fractures substantially increase disability and mortality among older adults^1,2,3. With the intensification of global population aging, osteoporosis has become a serious public health issue⁴. In China, the prevalence of osteoporosis in individuals aged 60 years or older is as high as 32%, creating a substantial and increasing clinical and socioeconomic burden.

Currently, the main treatment strategies for senile osteoporosis (SOP) in modern medicine include calcium and vitamin D supplementation, use of anti-resorptive drugs (such as bisphosphonates, RANKL-targeting monoclonal antibodies), and anabolic agents^5,6. While these therapies can effectively increase bone mineral density (BMD) and reduce fracture risk, they still face numerous challenges in long-term use. For example, bisphosphonates may lead to osteonecrosis of the jaw or atypical femoral fractures⁷, while agents such as teriparatide and denosumab are limited by high cost and potential rapid bone loss after discontinuation⁸. Therefore, exploring safer, more economical, and more suitable alternatives or complementary therapies for long-term management holds significant clinical importance.

Traditional medicine often categorizes osteoporosis under the scope of "bone wilting" (Gu Wei) or "bone withering" (Gu Ku). The Su Wen · Wei Lun states: "The kidney governs the bones and marrow... When kidney qi is hot, the lumbar spine cannot be raised, the bones wither, and the marrow diminishes, leading to bone wilting," establishing kidney deficiency as the core pathogenesis⁹. The kidney stores essence, governs the bones, and generates marrow. The warming and propelling functions of the primordial yang within the kidney are fundamental to robust bones and balanced metabolism. Kidney-yang deficiency leads to insufficient essence and blood, malnourishment of the marrow, and bones that are insufficiently nourished and weakened, becoming fragile. Clinical manifestations often include cold pain in the lumbar spine, soreness and weakness, aversion to cold, and cold limbs¹⁰. Therefore, warming and tonifying kidney-yang has become an important principle in TCM for preventing and treating kidney-yang-deficient osteoporosis¹¹.

Weishen Decoction (also known as Weishen Pill) originates from Liu Wansu's Suwen Bingji Qiyi Bao Ming Ji from the Jin Dynasty, originally indicated for "impairment of the liver and kidney affecting the spleen, poor digestion of food, and low back pain preventing rising¹¹." The formula uses Eucommia bark (Du Zhong) and Psoralea fruit (Bu Gu Zhi) as the sovereign herbs to warm the kidney, strengthen yang, and fortify tendons and bones; Dodder seed (Tu Si Zi), Fenugreek (Hu Lu Ba), and Cyathula root (Chuan Niu Xi) as minister herbs to tonify the liver and kidney and dispel wind-dampness; assisted by Saposhnikovia root (Fang Feng), Dioscoreae hypoglaucae rhizoma (Bi Xie), Tribulus fruit (Bai Ji Li), and Cinnamon bark (Rou Gui) to dispel wind-dampness, benefit the lower jiao, pacify the liver and subdue yang, and warm and unblock the channels. Together, these herbs are traditionally considered to synergistically warm and tonify kidney-yang and replenish essence to strengthen bones. Preliminary animal experiments have shown that Weishen Decoction may improve bone metabolism and promote bone formation by modulating signaling pathways, including TGF-β/Smad2 and MAPK¹². However, in clinical practice, this formula is most often used in combination with Western medicine. There is a lack of high-quality, rigorously designed clinical research evidence to support its efficacy and safety as a monotherapy for kidney-yang deficient senile osteoporosis.

To clarify the positioning of Weishen Decoction monotherapy, this paper compares it with mainstream clinical interventions. Conventional pharmacotherapy mainly includes bisphosphonates, denosumab, and teriparatide, which may be used with or without calcium and vitamin D supplements. These regimens can effectively reduce fracture risk and deliver reliable long-term efficacy, yet they have notable drawbacks. They may cause severe adverse reactions such as osteonecrosis of the jaw and atypical femoral fractures, and are associated with high costs and poor tolerability in some elderly patients. In addition, rapid bone loss commonly occurs after discontinuation of denosumab. Although calcium and vitamin D supplementation alone are safe and affordable, it exerts a limited effect on fracture prevention among elderly individuals with adequate vitamin D status^5,6. It is merely an adjunctive therapy rather than a disease-modifying treatment.

Another common approach is combined therapy with Chinese herbal formulas and conventional pharmacotherapy, which helps relieve clinical symptoms and reduce the dosage of Western drugs. Nevertheless, such add-on designs are confounded by background treatments, making it impossible to identify the independent therapeutic effect of herbal medicines. Furthermore, most relevant studies lack rigorous blinding, placebo control, and standardized criteria for TCM syndrome differentiation. For this reason, the true efficacy of kidney-tonifying herbal formulas, including Weishen Decoction, when used alone, remains unclear. There is therefore an urgent clinical need to verify whether standardized Chinese herbal formulas can serve as effective monotherapies, offering an alternative for patients who prefer pure TCM treatment or have contraindications to conventional Western medications.

This study adopts a placebo-controlled monotherapy design without calcium and vitamin D supplementation for the following reasons. First, it enables an unbiased assessment of the standalone efficacy of Weishen Decoction while eliminating confounding factors from background treatments. Second, no high-quality clinical trials have yet to confirm the independent effects of Weishen Decoction in this patient population, and a placebo-controlled design can yield the most rigorous evidence. Third, given the 12-week intervention period and close monitoring throughout the trial, withholding calcium and vitamin D was considered ethically acceptable under the study’s eligibility criteria and monitoring procedures. This design aims to address a key clinical question: Can monotherapy with Weishen Decoction improve clinical symptoms, pain severity, bone metabolism, and bone mineral density in elderly patients with senile osteoporosis of kidney-yang-deficiency pattern?

This study intends to fill the research gap. To our knowledge, this is the first clinical trial to evaluate the efficacy and safety of Weishen Decoction, used alone (without conventional anti-osteoporosis medications), in senile osteoporosis with a kidney-yang-deficiency pattern. The findings will provide preliminary evidence to support the precise clinical application of this formula and inform the design of subsequent confirmatory clinical trials.

Protocol

This study was performed in line with the principles of the Declaration of Helsinki. The study was approved by the Ethics Committee of Xuzhou Central Hospital (approval no. XZXY-LK-20230320-037). The trial was registered in the National Medical Research Registration System (No.: MR-32-23-014328).

Trial design

This was a prospective, single‑center, randomized, double‑blind, placebo‑controlled clinical trial designed to evaluate the clinical efficacy and safety of Weishen Decoction monotherapy in kidney-yang-deficient senile osteoporosis.

Recruitment and enrollment

Participants were recruited from the outpatient clinic of the Department of Orthopedics and TCM at Xuzhou Central Hospital between April 2023 and September 2024. A research coordinator screened electronic medical records daily for patients aged 60–80 years with diagnostic codes for osteoporosis (M80–M81) and presenting symptoms of back pain, soreness, and weakness in the waist and knees. Potentially eligible patients were then contacted by telephone using a standardized script that explained the study's purpose, the 12-week, double-blind, placebo‑controlled design, the absence of background calcium or vitamin D supplementation, and the availability of rescue treatment if needed. Patients who remained interested were scheduled for a screening visit. At screening, written informed consent was obtained from all participants before any study‑specific procedures. A screening log was maintained to record all contacted patients, reasons for exclusion, and those who declined participation. After consent, a fasting blood sample was drawn to measure serum 25‑hydroxyvitamin D₃ (a concentration≥20 ng/mL was required for inclusion), calcium, phosphorus, and bone turnover markers (PINP, β‑CTX, OC) using an automated biochemical analyzer. A dual‑energy X‑ray absorptiometry (DXA) device was used to measure bone mineral density at the lumbar spine (L1–L4) and left femoral neck. TCM syndrome differentiation was performed independently by two attending TCM physicians using a standardized case report form (CRF); any disagreement was resolved by discussion with a third senior TCM physician. All inclusion and exclusion criteria were checked against a preprinted checklist. Eligible participants were then scheduled for a baseline assessment within 7 days before randomization.

Sample size calculation

The sample size was calculated based on the primary outcome—the total effective rate (dichotomous outcome). According to two previously published meta‑analyses of TCM interventions for primary osteoporosis^13,14, the reported total effective rates (based on TCM syndrome score reduction) for kidney‑tonifying herbal formulas ranged from approximately 60% to 75% in treatment groups and from 35% to 50% in placebo or control groups. Based on these estimates, effective rates of 66% for the Weishen Decoction group and 40% for the placebo group were assumed. Using a two‑sided α = 0.05 and β = 0.20 (power = 80%), sample size estimation for comparing two independent proportions was performed with dedicated sample size calculation software. The following parameters were entered: p₁ = 0.66, p₂ = 0.40, α = 0.05, power = 0.80, allocation ratio N2/N1 = 1. The calculation indicated that 33 patients per group were needed. Considering an approximate 10% dropout rate, a total sample size of 72 patients was ultimately determined, with 36 patients in each group. The software output and analysis settings were saved as a PDF and stored in the trial master file.

Randomization and blinding

A stratified block randomization method was employed. Stratification factors were age group (60–70 years vs. 71–80 years) and sex (male vs. female). A fixed block size of 4 was used. An independent statistician not involved in participant recruitment, treatment, or efficacy evaluation used randomization software to generate the allocation sequence. The following procedure was followed: (1) a new blank dataset was created with 72 rows; (2) stratification variables (age group and sex) and a sequential participant ID (1–72) were entered; (3) within each stratum, a uniform random number between 0 and 1 was generated; (4) participants were sorted by stratum and by the random number; (5) within each block of size 4, the first two were assigned to Weishen Decoction (code A) and the next two to placebo (code B); (6) the final allocation table was printed. The random sequence was printed and sealed in sequentially numbered opaque envelopes. These envelopes were stored in a locked cabinet in the hospital's central pharmacy, accessible only to the dispensing pharmacist, who was not involved in any other trial procedures. After enrollment and baseline assessment, the research coordinator assigned the next available participant ID (in ascending order) and retrieved the corresponding envelope from the pharmacy. The envelope was opened by the pharmacist only after the participant had completed all baseline assessments and eligibility had been confirmed. The pharmacist then prepared the study medication according to the allocation code and recorded the assignment on a secure allocation log (kept in a separate locked file). The study drugs (Weishen Decoction granules and the matching placebo) were identical in appearance, odor, packaging, and weight (each sachet weighed approximately 12.05 g). The pharmacy prepared a 4‑week supply of study medication for each participant according to the randomization envelope. For each participant, a set of labeled containers (one per 4‑week interval) was filled with the allocated sachets. Each container label included the participant ID, container number (e.g., W1, W2, W3 for weeks 1–4, 5–8, 9–12), and the instruction “Take one sachet twice daily after meals.” A separate dispensing log recorded participant ID, container number, number of sachets dispensed (28 per container), date of dispensing, and the dispensing pharmacist's initials. The log was signed and dated by both the pharmacist and a second independent pharmacy technician who verified the count. Participants, clinical investigators (responsible for enrollment, treatment, and follow‑up), efficacy evaluators, and data statisticians were all blinded to group assignments, which remained concealed until database lock and completion of the prespecified analyses. No unplanned unblinding events occurred during the study.

Diagnostic criteria

Western medical diagnosis of osteoporosis was based on the Guidelines for the Diagnosis and Treatment of Primary Osteoporosis (2022)¹⁵. Dual‑energy X‑ray absorptiometry was used to measure bone mineral density at the lumbar spine (L1–L4) or femoral neck, and a T‑score ≤−2.5 was used to confirm the diagnosis¹⁶. TCM diagnostic criteria for the kidney‑yang-deficiency pattern followed the Expert Consensus on TCM for Prevention and Treatment of Primary Osteoporosis (2020)¹⁶. The main symptoms were cold pain in the back and waist, and soreness and weakness of the waist and knees. Secondary symptoms included aversion to cold and a preference for warmth (aggravated by cold), as well as frequent urination or nocturia. Tongue and pulse findings included a pale, swollen tongue with a white, slippery coating and a deep, thready or slow pulse. Diagnosis required all main symptoms plus at least one secondary symptom, combined with the tongue and pulse presentation. Each symptom was quantified to calculate a total TCM syndrome score. According to the Expert Consensus on TCM for Prevention and Treatment of Primary Osteoporosis (2020)¹⁷, primary symptoms (cold pain in the back and waist, soreness and weakness of the waist and knees) were scored on a a four-level scale scored as 0, 2, 4, or 6 (0 = none, 2 = mild, 4 = moderate, 6 = severe), with the severity of cold pain in the back and waist anchored to VAS scores (mild: 1–3; moderate: 4–6; severe: 7–10). Secondary symptoms (limited lumbar activity, aversion to cold and preference for warmth, frequent urination or nocturia) were scored on a 0–1–2–3 scale (0 = none, 1 = mild, 2 = moderate, 3 = severe). All evaluators were trained on these criteria and pilot‑tested on 10 patients before the study to ensure inter‑rater consistency (intraclass correlation coefficient ≥0.85).

Inclusion, exclusion, and withdrawal criteria

Inclusion criteria were: age 60–80 years; meeting the above Western medical diagnostic and TCM kidney‑yang-deficiency pattern criteria; no use of drugs affecting bone metabolism (e.g., bisphosphonates, teriparatide, denosumab) within 3 months prior to enrollment; stable vital signs, clear consciousness, ability to cooperate with scale assessments and follow‑up; and voluntary participation with signed informed consent. Exclusion criteria were: secondary osteoporosis (e.g., hyperparathyroidism, Cushing’s syndrome, long‑term glucocorticoid use); comorbid severe primary diseases of the ardiac, hepatic, renal, or hematologic disease, or malignant tumors; a history of hypersensitivity or known allergy to any ingredient of the study drug; comorbid lumbar compression fractures, severe spinal deformities, or a history of joint replacement affecting BMD measurement affecting the accuracy of BMD measurement; a cognitive or psychiatric condition that precluded informed consent or completion of study procedures; and concurrent participation in another clinical study. Discontinuation and withdrawal criteria were: occurrence of serious adverse events deemed by the investigator to preclude continuation; poor participant compliance (medication adherence rate <80% or loss to follow‑up); withdrawal of consent; and occurrence of clinical events that required standard treatment and urgent intervention during the study.

Treatment methods

This study did not include conventional pharmacotherapy (background treatment: calcium and vitamin D). Participants received either Weishen Decoction or a matching placebo to assess its independent efficacy. The Weishen Decoction group received oral Weishen Decoction granules (prepared by a Chinese pharmaceutical company; Batch No.: 20240217). The granules were manufactured using a standardized water extraction and spray‑drying process. The daily crude herb equivalent (total 111 g) yielded approximately 20.5 g of extract after spray‑drying. After adding dextrin (15% w/w), the total daily granule weight was approximately 24.1 g, divided equally between two sachets (each containing approximately 12.05 g of granules, equivalent to 55.5 g of crude herb and 10.25 g of dry extract per sachet). Participants dissolved one sachet in 150–200 mL of warm water and consumed it after breakfast and again after dinner. The control group received oral matching placebo granules identical in appearance, color, odor, and taste (Batch No.: 20240211; made from dextrin, caramel, and food coloring, without pharmacological activity), packaged identically and with the same dosing regimen. The treatment course for both groups was 12 weeks. Throughout the 12‑week treatment period, patients were monitored at weeks 4, 8, and 12. Any participant who developed a new fragility fracture, significant worsening of back pain limiting mobility, or a clinically meaningful decline in functional status was to be withdrawn from the trial and referred for standard care osteoporosis management. No such withdrawals occurred.

Adherence monitoring

Medication adherence was assessed using a combined method of sachet count and patient diary. A 4-week twice-daily supply should ordinarily contain 56 sachets. Participants were instructed to return all sachets, used and unused, at each follow‑up visit (weeks 4, 8, and 12). At each visit, study staff counted the returned sachets and recorded the count on a standardized adherence log.

The adherence rate for each interval was calculated as:

where "number of sachets actually taken" was derived from (sachets dispensed at previous visit) − (sachets returned at current visit).

Each participant also received a paper diary to record the date and time of each sachet intake. Diaries were reviewed and signed by the study coordinator at each follow‑up visit. Discrepancies between diary entries and sachet counts were reconciled through participant interviews; if unresolved, the more conservative estimate was used. An adherence rate of ≥80% over the entire 12-week period was considered acceptable. Participants with adherence <80% at week 4 or week 8 received additional counseling; if adherence remained <80% at the subsequent visit, they were considered non‑adherent and withdrawn from the per‑protocol analysis (but were still followed for safety and included in the intention‑to‑treat analysis). After a missed dose, participants were instructed not to double the next dose but to resume the regular schedule.

Observation measures and evaluation methods

The primary outcome was the total effective rate, defined as the reduction in TCM syndrome score. TCM syndrome scores were assessed before treatment and after 12 weeks of treatment. Using the Nimodipine method ([(baseline score − post-treatment score) / baseline score] × 100%), “markedly effective” was defined as a syndrome score reduction rate ≥70%, “effective” as 30% ≤ reduction rate <70%, and “ineffective” as reduction rate <30%. The total effective rate was calculated as (number of participants classified as markedly effective or effective) / total number of cases × 100%. Key secondary outcomes were the change in total TCM syndrome score (continuous variable) and the change in low back pain intensity measured by the Visual analog scale (VAS, 0–10 scale)¹⁷. Exploratory secondary outcomes included changes in bone mineral density (BMD) at the lumbar spine and femoral neck, changes in serum bone metabolism markers (PINP, β‑CTX, OC, Ca, P, 25(OH)D₃, bone-specific alkaline phosphatase (BALP)), and safety indices. BMD was measured using a DXA device by the same certified technician, blinded to group assignment, at baseline (within 7 days before randomization) and at the post‑treatment follow‑up visit (within 12 weeks after treatment completion)^4,19. Fasting venous blood was drawn before treatment and after 12 weeks for measurement of bone metabolism markers using an automated electrochemiluminescence immunoanalyzer. Safety was assessed through continuous adverse event (AE) monitoring; scheduled laboratory tests (complete blood count, urinalysis, liver and kidney function tests, electrocardiography (ECG)) at baseline and at week 12; and physical examinations at each visit (weeks 4, 8, and 12). All AEs were collected via spontaneous reporting and active inquiry at each visit. Severity was graded using the

Common Terminology Criteria for Adverse Events (CTCAE).

Clinical safety instructions and stopping rules

An independent Data and Safety Monitoring Board(DSMB) consisting of a clinical pharmacologist, a geriatrician, and a biostatistician convened every 6 weeks to review all safety data. The following safety rules were predefined. Any serious adverse event (SAE)—defined as death, a life-threatening event, initial or prolonged hospitalization, persistent or substantial disability, or a congenital anomaly, or prolongation of existing hospitalization, persistent or significant disability, or congenital anomaly—was to be reported to the ethics committee within 24 hours and to the DSMB within 48 hours. Unblinding of the affected participant could be performed by the principal investigator only if knowledge of the treatment assignment was deemed essential for patient management. The unblinding procedure was managed by the central pharmacy, which maintained the allocation code in a sealed envelope. If an SAE was judged as possibly, probably, or related to the study drug, the DSMB would recommend discontinuation of the affected participant and, if multiple similar SAEs occurred, suspension of the entire trial. For non‑serious AEs, treatment could be continued at the investigator’s discretion; if an AE caused persistent discomfort or became moderate to severe (grade 2 or higher) and did not resolve within 7 days, the investigator could withdraw the participant from the study. The trial would be stopped early if (i) two or more SAEs were related to the study drug; (ii) a previously unrecognized serious toxicity emerged; or (iii) the DSMB recommended stopping due to futility or harm.

Data handling and statistical methods

All case report forms (CRF) were completed by trained study coordinators and independently entered twice into an electronic database by two independent data entry clerks. The two entries were compared using the software’s built‑in validation module; discrepancies were resolved by referring to the original source documents. A data query log was maintained. After the last participant completed the week‑12 visit and all queries were resolved, the principal investigator and the data manager locked the database. The locked database was exported to statistical analysis software for analysis. The syntax file containing all data transformations, variable labeling, and analysis commands (including the χ² test for the primary outcome, independent t‑tests for change scores, and ANCOVA sensitivity analyses) was saved and archived with the trial master file. Statistical analysis was conducted on both the Full Analysis Set and the Per‑Protocol Set; because no patients withdrew and no major protocol deviations occurred, the two sets were identical. For the primary outcome (total effective rate), the χ² test was used. For continuous secondary outcomes, change scores (post‑treatment minus baseline) were compared between groups using independent‑sample t‑tests (for normally distributed changes) or Mann‑Whitney U tests (for non‑normally distributed changes). As a sensitivity analysis, analysis of covariance (ANCOVA) was performed to adjust for baseline values, yielding consistent results. All statistical tests were two‑sided, with P < 0.05 considered statistically significant. No interim analysis was planned or performed.

Results

Participant flow, blinding validation, and follow-up completeness

Randomization and allocation

72 patients were randomized (36 to Weishen Decoction, 36 to placebo). All 72 received the assigned intervention; no protocol deviations occurred.

Blinding integrity

Blinding was not formally assessed (e.g., using the James Blinding Index). However, no unplanned unb...

Discussion

This study, through a rigorously designed randomized, double-blind, placebo-controlled trial, evaluated the clinical efficacy and safety of the traditional Chinese herbal formula Weishen Decoction, administered alone (without any conventional pharmacotherapy), in treating kidney-yang-deficient senile osteoporosis. The results indicate that after 12 weeks of intervention, compared to placebo, Weishen Decoction significantly improved patients' core clinical symptoms of kidney-yang deficiency and alleviated low back pai...

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
			Study interventions
Weishen Decoction granules	Beijing Kangrentang Pharmaceutical Co., Ltd., Beijing, China	Batch 20240217	Weishen Decoction granules
Placebo granules	Beijing Kangrentang Pharmaceutical Co., Ltd., Beijing, China	Batch 20240211	placebo simulant granules
			Bone and metabolism measurements
Discovery Wi	Hologic, Inc., Marlborough, MA, USA	N/A	dual-energy X-ray absorptiometry (DXA) device
Cobas e 601 module	Roche Diagnostics, Mannheim, Germany	N/A	automated electrochemiluminescence immunoanalyzer
Cobas c 701 module	Roche Diagnostics, Mannheim, Germany	N/A	automated biochemical analyzer
			Safety and routine laboratory tests
XN-9000	Sysmex Corporation, Kobe, Japan	N/A	automated hematology analyzer
Clinitek Atlas	Siemens Healthineers, Erlangen, Germany	N/A	automated urinalysis system
AU5800	Beckman Coulter, Brea, CA, USA	N/A	automated chemistry analyzer
CardioFax V6.0	Nihon Kohden, Tokyo, Japan	N/A	electrocardiograph
			Quality control
(not specified)	(not specified)	N/A	high-performance liquid chromatography (HPLC) system
			Software for trial management and analysis
PASS 15.0	NCSS, LLC, Kaysville, UT, USA	N/A	sample size calculation software
SPSS 22.0	IBM Corp., Armonk, NY, USA	N/A	randomization software
EpiData 3.1	The EpiData Association, Odense, Denmark	N/A	electronic database software
SPSS 22.0	IBM Corp., Armonk, NY, USA	N/A	statistical analysis software
			Supplies and consumables
(not specified)	(not specified)	N/A	sachets (packaging)
(not applicable)	(not applicable)	N/A	patient diary