Conditions: Type 2 Diabetes
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 46
Healthy volunteers: no

Brief summary:
Type 2 diabetes mellitus is a chronic metabolic disease that seriously affects patients worldwide, and it is always among the top 10 causes of death in Taiwan. To date, still many patients who take more than three kinds of oral hypoglycemic agents could not effectively control their glycohemoglobin levels in clinics. Hypoglycemia as well as weight gain are common side effect with insulin therapy, and many patients in Taiwan are not willing to receive insulin injection. It is common for diabetic patients treated with Chinese herbal medicine in China currently, and some therapeutic effects have been published in international journals. In this study, we will evaluate whether Chinese herbal medicine, YH1, enhances the glycemic control and is safe as add-on medication in poorly controlled type 2 diabetes patients.

A total of 46 poorly controlled type 2 diabetes patients with glycohemoglobin ≥ 7% from Endocrinology and Metabolism clinics or Internal Chinese Medicine clinics will be enrolled in this randomized double-blind placebo-controlled trial. Subjects will be randomly assigned to receive either YH1 (6 g) or the placebo three times per day for 12 consecutive weeks. All subjects in both groups will also continuously receive their oral hypoglycemic agents without any dose or medicine change. During this 12-week period, the glycohemoglobin, fasting plasma glucose, 2h postprandial glucose, waist circumference, body weight, and body mass index will be assessed. In addition, insulin resistance, β -cell function, lipid profile, liver and renal function will also be evaluated. Independent statisticians will perform the data analysis at the end of the trial.

Detailed description:
The YH1 in one batch number was used, manufactured by Sun Ten Pharmaceutical Co., LTD., a renowned GMP manufacturer of concentrated herbal extract granules conforming to international standards. The YH1 was prepared in small granules, including concentrated herbal extract granules of Rhizoma Coptidis (50%) and SLBZS (50%). Both medicines have already been approved by the Ministry of Health and Welfare in Taiwan as ethical drugs. YH1 granules were packed in aluminum foil packages. The placebo was also prepared as granules by Sun Ten Pharmaceutical Co., LTD., and the packaging of the placebo was identical to that of YH1. The chemical composition of YH1 was analyzed and profiled by using a high performance liquid chromatography (HPLC) with photodiode array (PDA) detection. Fourteen components, allantoin, atractylenolide III, berberine, coptisine, ginsenoside Rb1, ginsenoside Re, ginsenoside Rg1, glycyrrhizin, liquiritin, pachymic acid, palmatine, platycodin D, magnoflorin and quercitrin, were simultaneously used in the qualitative analysis under the developed HPLC-PDA method. As for the quantitative detection, each gram of YH1 contained 20.05 mg berberine.

Arms:
arm 1: YH1 with one batch number was manufactured by Sun Ten Pharmaceutical Co., Ltd., a renowned manufacturer of concentrated herbal extract granules conforming to the standards of good manufacturing practices (GMP) in New Taipei City, Taiwan. YH1 contains Rhizoma Coptidis (50 %) and Shen-Ling-Bai-Zhu-San (SLBZS) (50 %). SLBZS consists of Radix Ginseng, Poria, Rhizoma Atractylodis macrocephalae, Semen Lablab album, Rhizoma Dioscoreae, Embryo Nelumbinis, Radix Platycodonis, Semen Coicis, Fructus Amomi, Fructus Jujubae, and Radix Glycyrrhizae at a 3:3:3:2.3:3:1.5:1.5:1.5:1.5:1.5:3 ratio. Subjects in the YH1 group orally ingested two packages of granules (3 g/package) three times daily with warm water after a meal for 12 consecutive weeks. arm 2: The placebo was also prepared as granules by Sun Ten Pharmaceutical Co., Ltd., and the packaging of the placebo was identical to that of YH1. Subjects in the placebo group orally ingested two packages of granules (3 g/package) three times daily with warm water after a meal for 12 consecutive weeks.

Interventions: intervention 1: YH1 group intervention 2: placebo group
Intervention descriptions: intervention 1: Participants were randomly assigned 1:1 to receive either YH1 or placebo for 12 consecutive weeks. intervention 2: Participants were randomly assigned 1:1 to receive either YH1 or placebo for 12 consecutive weeks.

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
The Efficacy and Safety of Chinese 
Herbal Medicine YH1 as Add-On 
Medication in Poorly Controlled Type 2 
Diabetes Patients 
 
 
 
 
 
 
 
ClinicalTrials.gov NCT02752880 
 
Date of the Document: January 23, 2019 
 
 


Study Protocol and Statistical Analysis Plan  
Trial design 
This study was a randomized, double-blind, placebo-controlled trial. All eligible 
subjects were 1:1 randomly assigned to receive either YH1 or placebo for 12 
consecutive weeks, and all subjects continuously received their OHAs without any 
dose or medicine change. The primary objective was to evaluate whether YH1 
enhances glycemic control and is safe as an add-on medication in the study population. 
The Committee on Research Ethics of the Chang Gung Memorial Hospital in Taiwan 
approved the study (No: 104-7934A3, 105-7009C, 106-0917C). Because of difficulties 
in enrolling participants, we expanded the eligibility criteria once, such as HbA1c (from 
≧ 9 % to > 7 %), BMI (from ≧ 24 kg/m2 to ≧ 23 kg/m2), and added an additional 
branch of hospital for recruiting subjects. All participants provided their informed 
consents prior to participation.  
 
Participants 
Patients who met the following inclusion criteria were referred from 
endocrinology and metabolism clinics to Chinese medicine clinics to join this study: 1) 
diagnosed as type 2 diabetes and treated with ≥ 3 classes of OHAs with persistent (> 6 
months) poorly glycemic controlled (HbA1c >7.0 % or 53 mmol/mol); 2) 20–75 years of 
age; 3) BMI ≥ 23 kg/m2.  


The exclusion criteria were as follows: 1) type 1, gestational, or other specific 
types of diabetes; 2) received insulin therapy in the past three months; 3) serious 
gastrointestinal (GI) tract diseases, such as peptic ulcers or GI tract bleeding; 4) 
experienced stressful situations, including diabetic ketoacidosis, nonketotic 
hyperosmolar diabetic coma, severe infection, or surgery in the previous month; 5) 
suffered from hepatic insufficiency with alanine aminotransferase (ALT) two times the 
upper limit of normal or renal insufficiency with estimated glomerular filtration rate 
(eGFR) < 60; 6) uncontrolled hypertension (blood pressure ≥ 160/100 mmHg); 7) 
mental illness, abused or addicted to alcohol, psychoactive substances or other drugs; 
8) pregnant, lactating, or planning to become pregnant; 9) hemoglobin disease or 
chronic anemia; 10) underlying conditions that could lead to poor compliance; 11) 
history of cerebrovascular disease or myocardial infarction; 12) undergone Chinese 
medicine treatment in the past two weeks. 
 
Study medication 
The YH1 in one batch number was used, manufactured by Sun 
Ten Pharmaceutical Co., LTD., a renowned GMP manufacturer of concentrated herbal 
extract granules conforming to international standards. The YH1 was prepared in small 
granules and packed in aluminum foil packages. The placebo was also prepared as 


granules by Sun Ten Pharmaceutical Co., LTD., and the packaging of the placebo was 
identical to that of YH1. The chemical composition of YH1 was analyzed and profiled 
by using a high performance liquid chromatography (HPLC) with photodiode array 
(PDA) detection (Fig 1). Fourteen components, allantoin, atractylenolide III, berberine, 
coptisine, ginsenoside Rb1, ginsenoside Re, ginsenoside Rg1, glycyrrhizin, liquiritin, 
pachymic acid, palmatine, platycodin D, magnoflorin and quercitrin, were 
simultaneously used in the qualitative analysis under the developed HPLC-PDA 
method. As for the quantitative detection, each gram of YH1 contained 20.05 mg 
berberine. 
Fig 1. 2D-HPLC fingerprint of YH1. (A) HPLC of 14 standards (B) HPLC of YH1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Interventions 
The subjects who provided their informed consents were randomly and equally 


assigned to receive either YH1 or the placebo for 12 consecutive weeks. Subjects in 
the two groups were orally administered two packages of granules (3 g / package) 
three times daily with warm water after a meal. The dose of the OHAs was stable for 
at least three months before enrollment and remained unchanged throughout the 
study. Education for lifestyle management of type 2 diabetes on the use of medications 
was provided to both groups. 
During the 12-week period, patients were assessed at 0, 2, 4, 8 and 12 weeks. In 
each session, all subjects received symptom assessment and a physical examination 
including body weight, BMI and waist circumference. In addition, drug compliance and 
any side effects were also recorded. The HbA1c, FPG, and 2hPG were measured at 0, 4 
and 12 weeks. Insulin resistance index, β-cell function index, lipid profile, hepatic and 
renal function were assessed at 0 and 12 weeks. 
 
Outcomes 
The primary efﬁcacy endpoint was the percentage of change in HbA1c levels from 
the baseline at 12 weeks. The HbA1c was measured in the laboratory medicine 
department of Chang Gung Memorial Hospital by high-performance liquid 
chromatography. The secondary efﬁcacy endpoints were the percentage of changes of 
several parameters from baseline, including fasting and postprandial glycemic level, 


homeostatic model assessment (HOMA) of insulin resistance (IR) and HOMA-β, lipid 
profile, body weight and waist circumference, and clinical symptoms. 
The safety endpoints were the incidence rates of adverse events, such as any 
undesirable or unintended symptoms, and laboratory test abnormalities of alanine 
aminotransferase (ALT) and serum creatinine, regardless of the causal relationship 
with the study drug. Adverse events were recorded throughout this trial by direct 
questioning. 
 
Randomization and blinding 
Randomization codes were generated with a computer program (SAS version 9.2, 
Cary, NC) by an independent statistician. Study drugs prepared by Sun 
Ten Pharmaceutical Co., LTD. were packed and numbered according to the random 
coding form, which was concealed in an opaque envelope after randomization. The 
envelope was not decoded until the end of the trial. Study drugs were provided based 
on the assigned numbers according to the visit sequence and study drug number 
sequence. During the trial, both the clinicians and patients were unaware of the 
grouping.  
 
Statistical analysis 


The comparison of clinical characteristics between the two groups was based on 
Wilcoxon rank-sum test for continuous variables, and Fisher’s exact test was used to 
evaluate the associations between categorical variables. Longitudinal analysis of HbA1c 
change between groups was based on repeated measure ANOVA using SPSS 21.0 
software (SPSS Inc., Chicago, IL). Other statistical analyses were performed in R V.3.4.3 
(http://www.r -project.org). A two-tailed p <0.05 was considered statistically 
significant.