The VA/D supplementation trial is being conducted in a network of 4 TB clinics in Qingdao and Linyi city in Shandong province in China. Together, these clinics provide care for approximately 5,000 active pulmonary tuberculosis patients per year and nearly 10% have DM. These four clinics are the sites for study recruitment, delivery of the VA and/or VD intervention, and all research visits.
VA and/or VD supplementation is delivered by the physicians, together with the nurses, social workers to take care of the patients. The medical team provides comprehensive medical care, including TB and DM pharmacotherapy.
VA/D supplementation scheme
This is a 2-by-2 factorial-design intervention trial. Active pulmonary tuberculosis patients with diabetes mellitus are offered onsite TB and DM evaluation and treatment by primary care providers, and are free to choose whether to receive VA/D supplementation. Primary care providers receive special training by the project team, including the related knowledge of TB and DM, especially the association between TB and DM; the related nutritional deficiencies and the role of micronutrients in cell-mediated immunity.
Once sign the informed consents, the patients will be randomly assigned to VA (2000 IU daily retinol on top of normal pharmacotherapy) or VD (400 IU daily cholecalciferol on top of normal pharmacotherapy) or VAD (2000 IU daily retinol plus 400 IU daily cholecalciferol on top of normal pharmacotherapy) or control (placebo on top of normal pharmacotherapy) group.
Trial inclusion and exclusion criteria
Potential trial subjects are eligible for inclusion if they are affected with active pulmonary tuberculosis and have fasting plasma glucose (FPG) of ≥126 mg/dL or 2-hour glucose level of 200 mg/dL or above by OGTT; have no history of previous anti-tuberculosis treatment and oral hypoglycemic drugs or insulin used; plan to initiate onsite anti-tuberculosis and DM treatment at the TB clinic within the next six months; attend their TB clinic after hospitalization once or twice per month to receive supplementation pill and physical examination; plan to stay in local place for 2 years. Participants are excluded if they are unable or unwilling to provide informed consent; are drug resistant at baseline or during the follow up; pregnancy; lactation; use of corticosteroids or supplements containing vitamin A or vitamin D during the previous month; chronic renal failure as indicated by elevated serum uric acid or creatinine concentrations; and clinical signs of neoplasm and congestive heart failure.
Approvals and data safety and monitoring
The trial was approved by Ethics Committee of the affiliated hospital of Medical College of Qingdao University. All participants provide written informed consent. Besides of VA and/or VD supplementation, we are giving nutritional and behavioral suggestion and instruction that is highly integrated with normal clinical care to all the subjects. Also, we established a data safety and monitoring plan, which requires interim analyses after every twenty patients are enrolled.
Medical providers in the four TB clinics are asked to invite all patients initiating on-site anti-TB and DM treatment to consider enrolling in the trial. Subjects also are referred by other subjects or through the project group. The initial steps in subject recruitment include a brief screening survey, informed consent, and in depth verification of eligibility using medical records and discussion with providers.
Random-number tables are used to allocate subjects to the VA intervention arm, VD arm, VAD arm or the placebo control arm.
The baseline assessment consists of an interview and physical measurement. Baseline fast blood glucose, results of urine toxicology tests, liver function test and other related clinical indexes are obtained by chart review. The baseline interview is conducted prior to vitamin supplementation initiation, and at this visit all subjects are invited to attend VA/D supplementation trial. Following completion of the baseline assessment, participants receive their assignment to one of the four arms.
Visit schedule and measures
Frequency and length of research visits during the 24 to 32 weeks (according to the anti-tuberculosis drug treatment period) intervention period are the same for subjects in each arm. We standardized the visit schedule to control for any improvement in adherence, possible side effects which might result from VA/VD supplementation alone. We use several measures to assess VA/VD adherence: self-report, pill count, and nursing records of directly observed doses and returned pill boxes.
Treatment-related side effects
A treatment side effect scale (which measures the degree of VA and/or VD treatment-related side effects) is administered at each monthly visit, and the results are given to medical providers. Side effects include fatigue, irritability, anorexia, headache, fever, insomnia, nausea, vomiting, and other common side effects.
Sample size and power calculations
We calculated the sample size on the basis of literature research in the related domain and analyzing the objective and indexes in this trial by using formula:
We calculated the needed sample size for the main indexes and selected the largest one. We will need 84 subjects in each arm to have 90% power to show significant difference among trial arms. Considering participants’ compliance, none response and withdraw, a sample size of 100 per arm is needed.
Planned statistical analyses
We hypothesize that effect of anti-TB and DM treatment in VA and/or VD arms will be better than the effect in the control arm. Descriptive statistics will be calculated and checked for balance in each arm in demographic, physical and other related measurements at baseline. Comparisons among the groups of pulmonary pathological damage, CD4+ T cell, HOMA-IR, etc., will be performed by Chi-square (categorical variables), F test (continuous variables, normal distribution) or Kruskal–Wallis H test (ranked data). Linear mixed-effects models will be used to analyze the main influencing factors.
We will also calculate anti-tuberculosis and diabetes treatment results, nutritional and immunologic indexes at three time points: before the supplementation (at the inclusion), 2 months after the supplementation, and at the end of the trial (6 to 8 months after the supplementation).
Study sample characteristics
Screening and baseline interviews began in Oct, 2012, and are ongoing. We here present the baseline characteristics of the first 37 subjects who have been enrolled and initiated on-site anti-TB and DM treatment: Of these, 8 were randomized to the VA arm, 10 to VD arm, 9 to VAD arm and 10 to the control arm (Figure ).
Flow chart of study recruitment and enrollment.
The sample is 91.9% male, 97.3% ethnic Han, with a mean age of 52 (Table ). 83.8% subjects have education level of senior high school or lower, 75.7% married, 48.6% employed. 75.7% subjects’ BMI were normal(18.5~24.99)with one patient being severe wasting, 5 patients being mild wasting and 3 patients being overweight.
Baseline characteristics of study sample (n =37)
At baseline, 94.6% of the sample had cough, 89.2% had expectoration, 29.7% had hemoptysis, 48.6% had fever, 75.7% had weak, 51.4% had night sweat, 21.6% had thoracalgia, 54.1% had chest stufly. As to pulmonary pathology inspected by CT, 73% of the sample had pulmonary cavity, 2.7% had infiltration. Admission biochemical examine showed that the mean fast plasma glucose concentration was 12.19 mmol/L, mean LDL-C level was 2.42 mmol/L, median TC concentration was 4.29 mmol/L, median TG concentration was 1.66 mmol/L, mean HDL-C level was 1.21 mmol/L.
Our intervention is feasible and can be implemented in a busy clinical setting. Staff at the four clinics worked collaboratively with the study team, and to date 37 participants have been enrolled from the four clinics. Health care providers communicate well with the medical director and research assistants, and nurses at each clinic record daily events on study calendars. To date, a total of 51 subjects have been screened (Figure ).
The VA/D program is acceptable to our patients. To date, 88% of all patients who were eligible for receiving VA/D supplementation and met study inclusion and exclusion criteria have chosen to participate. No participants have refused their randomization.
The core components of our VA/D program do not require additional staff over existing clinic operating models. We will provide subsidies for medical providers, nurses, or support group facilitators on support of the Natural Science Foundation of China (NSFC) and Danone Nutrition and Education fund. We pay the VA and VD supplements used for the study.