Efficacy, Safety and Response Predictors of Adjuvant Astragalus Therapy for Diabetic Kidney Disease (READY)

Efficacy, Safety and Response Predictors of Adjuvant Astragalus Therapy for Diabetic Kidney Disease (READY) - An Open-label Randomised Controlled Trial With Responder Regression Analysis

This add-on open-label randomised controlled pragmatic trial aims to:

1. evaluate the effect of add-on astragalus treatment on type 2 diabetic patients with stage 2 to 3 chronic kidney disease and macroalbuminuria.
2. estimate treatment effect, variance, recruitment rate, attrition rate and change in clinical manifestation including Chinese medicine syndrome for parameters optimisation and feasibility assessment for a subsequent phase III randomised controlled trial.
3. assess response predictors for efficacy and safety among type 2 diabetic patients with stage 2 to 3 chronic kidney disease and macroalbuminuria receiving add-on astragalus treatment

Study Overview

• Status: Unknown
• Conditions: Diabetic Kidney Disease; Diabetic Nephropathies
• Intervention / Treatment: Other: Routine medical care (active comparator); Drug: Astragalus Powder

Detailed Description

This add-on open-label randomised controlled pragmatic trial.

Sample size is calculated based on planned regression analysis. We believe an annual GFR benefit of 5 ml/min/1.73m2 is deemed significant clinically. 118 patients are therefore needed to offer a power of 70% to detect a GFR difference of 5 ml/min/1.73m2 over 48-week allowing 15% attrition rate for this study with a significance level of alpha equals to 0.05.

A trial management committee (TMC) formed by PA, Co-As and RA will centralise all the data of the trial. Co-As and RA will collect, clean and send the data of patients to TMC on a weekly basis. All data will be double entered to computer and cleaned before analysis to prevent data entry errors. All data transfer will be encrypted to protect patients' confidentiality. TMC will have regular meetings monthly with experts to discuss the progress of the trial. An independent Data Monitoring Board (DMB) will be invited to monitor the progress of the trial. DMB will advise ethics committee to terminate the trial if data is showing extreme benefits or harm. Detailed guidelines will be discussed and set by DMB.

Missing values will be imputed with last observation carried forward. Patient without a postrandomisation assessment for a particular efficacy endpoint will be excluded from the analysis of that endpoint.

Regression analysis will be used to compare the adjusted mean of eGFR, UACR, HbA1c, FBG, and other biomarkers at week 48 between groups and statistical significance. The adverse events will be analysed in a narrative manner. 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) comparison of baseline to end of treatment on eGFR and UACR; 2) comparison of baseline to end of treatment on other outcome measurements; 3) comparison of baseline to treatment midpoints on eGFR and UACR and 4) comparison of baseline to treatment midpoints on other outcome measurements.

Subgroup analysis will be performed for different age groups, gender chronic kidney disease stage and severity of albuminuria.

The dependent variable is the treatment response which is categorised into:

1. Improved or stabilised renal function, defined as eGFR after 48-week treatment being higher or equal to baseline.
2. Non-responder, defined as patients having eGFR decreased at a rate of less than 5 mL/min/1.73m2 after 48-week treatment compared to baseline.
3. Rapid deteriorating renal function, defined as eGFR of more than 5 mL/min/1.73m2 after 48-week treatment compared to baseline.

Potential prognostic variables (baseline values) include:

1. Demographics and past medical history: Age, gender, body mass index (BMI), systolic blood pressure, history and duration of smoking and alcohol consumption and others
2. Chinese medicine diagnosis: presence of Chinese medicine syndromes (e.g. spleen and kidney qi deficiency) based on the presentation of standardised and commonly documented signs and symptoms
3. Biochemical profile

• Study Type: Interventional
• Enrollment (Anticipated): 118
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Sydney CW TANG, MD, PhD; Phone Number: +852 22553879; Email: scwtang@hku.hk
• Study Contact Backup: Name: Kam Wa CHAN, BCM, MCM, MSc.(PH); Phone Number: +852 22553207; Email: chriskwcchan@hku.hk

Study Locations

• Hong Kong
  • Hong Kong, Hong Kong
    • Recruiting
    • Queen Mary Hospital
    • Contact: Sydney CW TANG, MD, PhD; Phone Number: +852 22553879; Email: scwtang@hku.hk
    • Contact: Kam Wa CHAN, BCM, MCM, MSc.(PH); Phone Number: +852 22553207; Email: chriskwcchan@hku.hk
  • Hong Kong, Hong Kong
    • Not yet recruiting
    • School of Chinese Medicine
    • Contact: Lixing LAO, MD, PHD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 35 years to 80 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• diagnosed with type 2 diabetes for at least 5 years;
• with an estimated glomerular filtration rate (GFR) ≥30 ˂90 mL/min/1.73m2 confirmed with repeat testing over three or more months calculated by the abbreviated MDRD study equation;
• persistent macroalbuminuria with spot urine albumin-to-creatinine ratio (UACR) ≥ 300 mg/g confirmed by at least 2 out of 3 consecutive first morning void urine samples;
• on stable dose of anti-diabetic drug including insulin for 12 weeks;
• on stable dose of angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker for 12 weeks; and
• willing and able to give written informed consent

Exclusion Criteria:

• with known history of glomerulonephritis, polycystic kidney disease, systemic lupus erythematosus, any suggestive evidence of nondiabetic glomerulopathy;
• with known history of kidney transplant;
• with concurrent severe disorders of heart, brain, liver, and hematopoietic system, tumor and mental disorder;
• with deranged liver function;
• poorly controlled blood pressure;
• with known history of intolerance or malabsorption of oral medications;
• with uncontrollable urinary infection;
• experiencing pregnancy; or
• participating in other clinical trial within 30 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Standard medical care; Angiotensin converting enzyme inhibitor or angiotensin receptor blocker and oral hypoglycemic agents or insulin	Other: Routine medical care (active comparator); Angiotensin converting enzyme inhibitor or angiotensin receptor blocker
EXPERIMENTAL: Add on astragalus powder; 3 grams of water soluble astragalus sachets (equivalent to 15g raw herbs) administrated orally on top of standard medical care for 48 weeks.	Other: Routine medical care (active comparator); Angiotensin converting enzyme inhibitor or angiotensin receptor blocker; Drug: Astragalus Powder; 3 grams of water soluble astragalus sachets (equivalent to 15g raw herbs) administrated orally on top of standard medical care for 48 weeks. Patients will have 5 days of medicine per week and will be advised to take the medicine once daily dissolved in boiling water in the first 5 days of the week.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in estimated GFR	Efficacy and safety	From baseline to 48 weeks after treatment
Change in spot urine albumin-to-creatinine ratio	Efficacy and safety	From baseline to 48 weeks after treatment

Secondary Outcome Measures

Outcome Measure	Time Frame
Change in glycated haemoglobin (HbA1c)	From baseline to 48 weeks after treatment
Change in urinary Cystatin C	From baseline to 48 weeks after treatment
Change in urinary monocyte chemotactic protein 1 (MCP-1)	From baseline to 48 weeks after treatment
Change in lipids	From baseline to 48 weeks after treatment

Other Outcome Measures

Outcome Measure	Time Frame
Change in biomarkers related to inflammation and fibrosis	From baseline to 48 weeks after treatment

Collaborators and Investigators

• Sponsor: The University of Hong Kong
• Collaborators: School of Chinese Medicine, The University of Hong Kong

Publications and helpful links

General Publications

• Chan KW, Kwong ASK, Tsui PN, Cheung SCY, Chan GCW, Choi WF, Yiu WH, Zhang Y, Wong MM, Zhang ZJ, Tan KCB, Lao L, Tang SCW. Efficacy, safety and response predictors of adjuvant astragalus for diabetic kidney disease (READY): study protocol of an add-on, assessor-blind, parallel, pragmatic randomised controlled trial. BMJ Open. 2021 Jan 12;11(1):e042686. doi: 10.1136/bmjopen-2020-042686.

Study record dates

Study Major Dates

• Study Start (ACTUAL): July 1, 2018
• Primary Completion (ANTICIPATED): June 30, 2022
• Study Completion (ANTICIPATED): December 31, 2022

Study Registration Dates

• First Submitted: May 13, 2018
• First Submitted That Met QC Criteria: May 13, 2018
• First Posted (ACTUAL): May 24, 2018

Study Record Updates

• Last Update Posted (ACTUAL): December 7, 2020
• Last Update Submitted That Met QC Criteria: December 3, 2020
• Last Verified: December 1, 2020

More Information

Terms related to this study

• Keywords: Chinese medicine; Pragmatic trial; Astragalus
• Additional Relevant MeSH Terms: Urologic Diseases; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Kidney Diseases; Diabetic Nephropathies
• Other Study ID Numbers: RE-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No