Study design

This is an assessor-blind, add-on, randomised, controlled, parallel, multicentre, open-label pragmatic clinical trial. The flow of study is summarised in figure 1.

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Figure 1

Flow of study.

Inclusion and exclusion criteria

Patients: (1) diagnosed with type 2 diabetes for at least 5 years; (2) with an estimated GFR≥30<90 mL/min/1.73 m² confirmed with repeat testing over 3 or more months calculated by the abbreviated Modification of Diet in Renal Disease (MDRD) study equation;27 (3) persistent macroalbuminuria with spot urine albumin-to-creatinine ratio (UACR) ≥300 mg/g confirmed by at least two consecutive first morning void urine samples; (4) aged between 35 and 80 years; (5) on a stable dose of antidiabetic drug including insulin for 12 weeks and (6) on a stable dose of ACE inhibitor or angiotensin receptor blocker for 12 weeks will be recruited.

Patients: (1) with a known history of glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus or any suggestive evidence of non-diabetic glomerulopathy; (2) with a known history of kidney transplant; (3) with concurrent severe disorders of the heart, brain, liver and haematopoietic system, tumour, mental disorder; (4) deranged liver function; (5) with poorly controlled blood pressure; (6) with a known history of intolerance or malabsorption of oral medications; (7) uncontrollable urinary infection; (8) experiencing pregnancy and (9) participating in other clinical trials within 30 days will be excluded.

Sample size calculation

Currently, there is no consensus on the sample size calculation for pilot studies. Previous studies suggested a sample size of 12–30 per arm.28–31 Since the primary objective of this trial is to explore the feasibility of a subsequent main study and have a preliminary evaluation on the effect of CM on patients with DN, the sample size calculation is based on control of the inflation factor (IF) to the estimation of sample size for the subsequent main study.31

The standard deviation used for sample size calculation for the main study could be underestimated by a pilot study and should be adjusted by an IF.31 IF is calculated based on the size of the pilot study and the confidence level of achieving at least the desired power in the main study. The actual achieved power of the main study depends on the nominal power set for the main study and the IF.

In order to be 95% confident (two-sided) that the subsequent main study actually achieves a power of 80% with nominal power set at 90% (ie, a 10% power forfeit), the IF should be <1.15. At IF=1.15, a sample size of 80 is therefore needed to have 95% one-sided confidence that the main study will achieve at least the nominal power to test the hypothesis that an add-on of the whole CM treatment programme could be more effective in stabilising the GFR among patients with DN when compared with having standard care alone. For subgroup analysis, a sample size of 25 patients per subgroup could achieve 80% one-sided confidence that the effect of stabilising GFR is different within subgroups of similar CM clinical pattern.

With five subgroups, a sample size of 148 patients is needed in this pilot trial to allow a 15% attrition rate.

Recruitment and setting

Patients are recruited from Queen Mary Hospital Specialist Renal Outpatients Clinic, Sai Ying Pun Family Medicine Specialty Clinic, Sai Ying Pun Jockey Club General Out-patient Clinic, Kennedy Town Jockey Club General Out-patient Clinic, Aberdeen Family Medicine Specialty Clinic, Aberdeen Jockey Club General Out-patient Clinic; and Diabetes Complication Screening Clinic and Renal Clinic of Tung Wah Hospital. Patients diagnosed with diabetes and CKD stage 2–3 with macroalbuminuria are referred to the principal investigator (PI), co-investigator (Co-I), or Chinese medicine practitioner (CMP) for further assessment. The aim, procedures, nature of study, possible side effects of the CM treatment programme and right of unconditional withdrawal are explained by PI or Co-I before written consent is obtained from each patient who agrees to take part in the study.

All patients will undergo a 2-week run-in period, during which they are asked to keep their medication dosage fixed. A blood sample will be taken and tested to check liver function (γ-glutamyltransferase, alanine transaminase (ALT), alkaline phosphatase, total protein, aspartate transaminase (AST), bilirubin, albumin) and renal function (sodium, chloride, urea, potassium, creatinine) in the Department of Pathology & Clinical Biochemistry of Queen Mary Hospital or local clinical laboratories of other hospitals. Patients are considered eligible for the study if their liver functions are normal.

A random sequence is generated by and encrypted with computer by an independent research assistant (RA). Sealed opaque envelopes containing an allocation sequence are sent to the outpatient clinics. The password of the sequence is kept in a sealed, duly-signed opaque envelope locked by RA and Co-I. The allocation sequence is concealed from PI and Co-Is responsible for patient screening, recruitment and assignment of CM subgroup stratification. Eligible candidates are randomised to either the active treatment arm or control arm. The allocation will be explained by the CMP I or II to the patient. The allocation will be masked from the outcome assessor. The participant could not be masked due to the nature of treatment. Since the clinical outcomes under investigation are objective, placebo effect should be minimised. The distribution of known and unknown confounding factors among the intervention group and control group is balanced by the randomisation.

Intervention and control

The intervention under investigation is a semi-individualised CM treatment protocol used on top of standard medical care. The programme consists of five different CM herbal formulations corresponding to five different subgroups of patients stratified by clinical manifestations according to classical CM theory:

A, for the subgroup of ‘spleen and kidney Qi deficiency’:

Radix Aucklandiae (Mu Xiang), Rhizoma Pinelliae Praeparatum (Fa Ban Xia), Rhizoma Atractylodis Macrocephalae (Bai Zhu), Poria (Fu Ling), Radix et Rhizoma Glycyrrhizae Praeparata cum Melle (Zhi Gan Cao), Fructus Amomi (Sha Ren), Pericarpium citri reticulatae (Chen Pi), Radix et Rhizoma Ginseng (Ren Shen), Radix Rehmanniae Praeparata (Shu Di Huang), Fructus Corni (Shan Zhu Yu), Rhizoma Dioscoreae (Shan Yao), Cortex Moutan (Mu Dan Pi), Rhizoma Alismatis (Ze Xie).

B, for the subgroup of ‘spleen and kidney Yang deficiency’:

Rhizoma Atractylodis Macrocephalae (Bai Zhu), Fructus Chaenomelis (Mu Gua), Radix Aucklandiae (Mu Xiang), Fructus Tsaoko (Cao Guo), Semen Arecae (Bing Lang), Radix Aconti Lateralis Praeparata (Hei Shun Pian), Poria (Fu Ling), Rhizoma Zingiberis (Gan Jiang), Radix et Rhizoma Glycyrrhizae Praeparata cum Melle (Zhi Gan Cao), Rhizoma Zingiberis Recens (Sheng Jiang), Fructus Jujubae (Da Zao), Radix Rehmanniae Praeparata (Shu Di Huang), Fructus Corni (Shan Zhu Yu), Rhizoma Dioscoreae (Shan Yao), Cortex Moutan (Mu Dan Pi), Rhizoma Alismatis (Ze Xie), Ramulus Cinnamomi (Gui Zhi).

C, for the subgroup of ‘spleen and kidney Qi and Ying deficiency’:

Radix et Rhizoma Ginseng (Ren Shen), Radix Astragali (Huang Qi), Radix Rehmanniae Praeparata (Shu Di Huang), Fructus Corni (Shan Zhu Yu), Rhizoma Dioscoreae (Shan Yao), Poria (Fu Ling), Cortex Moutan (Mu Dan Pi), Rhizoma Zingiberis Recens (Sheng Jiang), Fructus Jujubae (Da Zao).

D, for the subgroup of ‘liver and kidney Ying deficiency’:

Radix Rehmanniae Praeparata (Shu Di Huang), Fructus Corni (Shan Zhu Yu), Rhizoma Dioscoreae (Shan Yao), Poria (Fu Ling), Cortex Moutan (Mu Dan Pi), Rhizoma Alismatis (Ze Xie), Fructus Ligustri Lucidi (Nv Zhen Zi), Herba Ecliptae (Mo Han Lian).

E, for the subgroup of ‘Ying and Yang deficiency’:

Radix Rehmanniae Praeparata (Shu Di Huang), Fructus Corni (Shan Zhu Yu), Rhizoma Dioscoreae (Shan Yao), Poria (Fu Ling), Cortex Moutan (Mu Dan Pi), Rhizoma Alismatis (Ze Xie), Ramulus Cinnamomi (Gui Zhi), Radix Aconti Lateralis Praeparata (Hei Shun Pian), Fructus Ligustri Lucidi (Nv Zhen Zi), Herba Ecliptae (Mo Han Lian).

Patients with diabetic kidney disease provided consent are further assessed by the CMP and categorised into one of the five different CM subgroups based on the Guiding Principle of Clinical Research on New Drugs of Chinese Medicine.32 The CM diagnoses are based on clinical manifestation as follows:

A, for the subgroup of ‘spleen and kidney Qi deficiency’:

Primary manifestation: fatigue, shortness of breath, torpid intake, lumbago.

B, for the subgroup of ‘spleen and kidney Yang deficiency’:

Primary manifestation: fear of cold, fatigue, shortness of breath, torpid intake, lumbago.

C, for the subgroup of ‘spleen and kidney Qi and Ying deficiency’:

Primary manifestation: fatigue, lumbago, dry mouth, heat vexation.

D, for the subgroup of ‘liver and kidney Ying deficiency’:

Primary manifestation: dizziness or headache, lumbago, dry mouth, heat vexation.

E, for the subgroup of ‘Ying and Yang deficiency’:

Primary manifestation: fear of cold, lumbago, dry mouth, heat vexation.

Patients with at least one episode of all the primary manifestations of each CM subgroup listed above during the 2 weeks before consultation are considered eligible for the corresponding group. To enhance the specificity of categorisation, patients having multiple manifestations that fit more than one subgroup are excluded.

The treatment programme is originated from an existing clinical practice guideline being used in mainland China derived from expert consensus.18 Patients randomised to the intervention arm will receive the corresponding formulations on top of standard medication, as stated above. Minor adjustment of the herbs is allowed based on an individual's condition and determined by the CMP to reflect actual clinical practice. All patients continue their standard medications and follow-ups. Patients randomised to the control group will receive consultation from the CMP at baseline, study midpoint (week 24) and study end point (week 48) in addition to standard care. Patients will have 5 days of medicine per week and are advised to take the medication twice per day dissolved in boiling water in the first 5 days of the week.

Herbal safety

Herbal medicines with known toxicity that are listed in Schedule 1, Chapter 549, Chinese Herbal Medicines, Chinese Medicine Ordinance of Hong Kong are excluded. Soluble herbal granules prepared by PuraPharm are used in this study. The production process is in strict compliance with standards of Good Manufacturing Practice (GMP). The CM is prescribed and dispensed through the clinics of the School of Chinese Medicine, Li Ka Shing Faculty of Medicine or Clinical Trial Pharmacy of Queen Mary Hospital complying with the standard of practice of pharmacy. A fully registered CMP is responsible for clinical diagnosis and prescription. At week 6, patients will undergo liver function tests and brain natriuretic peptide (BNP) test for monitoring of liver toxicity and cardiotoxicity. To further ensure patient safety, we only recruit patients with stages 2–3 CKD who are more clinically stable to participate in the study.

Outcome measurement

The primary outcome measures are the changes in the estimated GFR and spot UACR between the baseline (week 0) and treatment end point (week 48). Secondary measures include changes from baseline (week 0) to end of treatment (week 48) in fasting blood glucose (FBG), HbA1c, serum BNP, fasting serum insulin, serum C peptide, serum fibroblast growth factor 23 (FGF23), urinary monocyte chemotactic protein-1 (MCP-1), urinary cystatin C, urinary nephrin, urinary TGF-β1 and urinary vascular endothelial growth factor (VEGF). A self-complete questionnaire is distributed to the participants to monitor occurrence of adverse events, and they are advised to inform the PI or RA immediately.

Estimated GFR, UACR, FBG, HbA1c and liver function test are ordered by the Renal Clinic and assessed by the Division of Clinical Biochemistry, Queen Mary Hospital or local clinical laboratories of other hospitals which are accredited by the College of American Pathologists. BNP, insulin, C peptide, FGF23, MCP-1, cystatin C, nephrine, TGF-β1 and VEGF assessment will be performed at PI's research laboratory by an independent RA. Estimated GFR is calculated using the abbreviated 4-variable MDRD study equation with serum creatinine, age, ethnicity and gender. Clinical presentations and CM syndromic diagnosis will be assessed in a structured consultation developed for this purpose. To ensure consistency and reliability of assessment and minimise bias from investigators across the study, patients will be assessed by the same CMP during each visit based on standard CM practice. Follow-up consultations are held for all patients weekly in the first month and monthly subsequently. Evaluation of outcomes will be performed at weeks 24 (on treatment) and 48 (end of treatment). The follow-up schedule is summarised below in table 1.

The baseline demographics including age, sex, body mass index, duration of diabetes, duration of diagnosed diabetic kidney disease and concurrent medications used are collected through the clinical management system of the Specialist Renal Outpatient Clinic. Patient flow measured as enrolled case per month and follow-up rate are recorded for the consideration of subsequent RCT design.

Handling of withdrawal and dropout

In order to maximise participants’ compliance, first, we have a thorough consent process for all participants with details of the study schedule, potential side effects of treatment, and the responsibilities of the participants explained. Second, we scrutinise potential participants carefully during a 2-week run-in period in order to exclude ineligible and low compliance participants before randomisation. Third, an independent email account and a direct telephone line associated with this clinical trial have been set up to enable active communication with patients. Moreover, extra visits will be arranged for patients if necessary. If any patient plans to withdraw or drop out, the study team will communicate with the patient to determine and resolve the problem in order to retain the participant.

Termination criteria

The trial will be terminated for a specific participant if she or he has: (1) presence of serious adverse effect(s) in the interventional group; (2) hypersensitivity towards Chinese herbal medicine and (3) participation in another clinical trial. The whole study will be terminated under the following circumstances: (1) presence of serious adverse effect(s) related to Chinese herbal medicine with supportive evidence and (2) completion of all follow-up assessments.

Serious adverse events include adverse events that result in death, require either hospitalisation or the prolongation of hospitalisation, are life-threatening, result in a persistent or significant disability/incapacity or result in a congenital anomaly/birth defect. Other important medical events, based on appropriate medical judgement, may also be considered serious adverse events if a patient's health is at risk and intervention is required to prevent an outcome mentioned.

Data analysis

Missing values, if any, will be imputed with regression. The analysis will follow the intention-to-treat approach. Patients without a postrandomisation assessment for a particular efficacy end point will be excluded from the analysis of that end point. SAS and SPSS will be used for the data analysis.

The demographics of each group will be presented as means. Sex will be presented as the male:female ratio. Regression analyses will be used to compare the adjusted mean of estimated GFR, UACR, HbA1c, FBG, BNP, insulin, C peptide, FGF23, MCP-1, cystatin C, nephrin, TGF-β1 and VEGF at week 48 between (1) the combination of all intervention groups and combination of all control groups, (2) individual treatment subgroup and its matching control group and (3) different control groups with the corresponding baseline values as covariates. Data will be presented as the difference in adjusted means between the intervention arm and control arm with a 95% CI and the corresponding p value. A change score analysis will be performed as supplementary analysis.

The adverse events are recorded based on the Common Terminology Criteria for Adverse Events V.4.03 and will be analysed in a narrative manner. The adverse events are categorised into five grades: grade (1) mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; no intervention indicated; grade (2) moderate; minimal, local or non-invasive intervention indicated; limiting age-appropriate instrumental activities of daily living; grade (3) severe or medically significant but not immediately life-threatening; hospitalisation or prolongation of hospitalisation indicated; disabling; limiting self-care activities of daily living; grade (4) life-threatening consequences; urgent intervention indicated; and grade (5) death related to adverse events. The percentage of all adverse events and the rate of attrition due to adverse events will be compared between intervention groups and control groups.

To minimise type I error inflation, the analysis will follow a hierarchical approach in the order of (1) individual treatment subgroup versus its control subgroup and (2) combination of all intervention groups versus the combination of all control groups as to avoid type I error inflation. The primary outcomes are the change of GFR and UACR.

Subgroup analysis will be performed for CKD stages 2 and 3 separately. Sensitivity analyses will be performed for (1) missing data imputed with regression, (2) missing data imputed with last-observation-carried-forward (LOCF) and (3) per protocol dropout of patients. Adverse events will be analysed case-by-case and presented descriptively.

Data management

A trial management committee is formed by the study team members. Co-Is and RA collect, clean and send the study data to the committee on a weekly basis. All data are double-entered to computer and cleaned before analysis to prevent data entry errors. All data transfer is encrypted to protect patients’ confidentiality. The committee holds meetings monthly with experts to discuss the progress of the trial.