Study Design
This is a single-center, randomized, double-blinded, placebo-controlled, parallel-group trial. This trial is designed to assess the efficacy and safety of TMDCD in relieving clinical symptoms of AA and reducing the dose of ICS. A total of 324 participants will be recruited at Beijing University of Chinese Medicine Third Affiliated Hospital. After the participants have been received written informed consent, they will be randomly divided into either Intervention group or control group in a 1:1 ratio. The Intervention group will be received TMDCD granules(one bag twice a day). And the control group will be received placebo granules (one bag twice a day) (Beijing Kangrentang Pharmaceutical Co., Ltd.). The researchers distributed the drugs in clinical dosage packages every 4 weeks ± 2 days and recovered the remaining drugs and empty packages. The subjects were required to fill in the medication registration form during drug administration, and the observing physicians filled in the drug distribution registration form and carefully asked the subjects about the medication status, judged the patient's compliance, and recorded adverse events. After the clinical trial is over, the remaining medicines shall be collected and destroyed according to the prescribed procedures, and the time, place, quantity, and method of destruction shall be recorded in detail.
To protect the interests of the subjects, during the treatment and follow-up period, the subjects in the intervention group and the control group can use budesonide/formoterol dry powder inhalation (160ug/4.5ug×60 actuations, produced by AstraZeneca, Sweden) as needed. To relieve symptoms of acute attacks and record after each use. For those with severe allergic symptoms, cetirizine hydrochloride tablets (10 mg/tablet, Yangzijiang Pharmaceutical Group Co., Ltd.) can be used as needed and recorded after each use. Note: Cetirizine hydrochloride tablets should be used as needed under the premise of meeting the dosage prescribed in the instructions.
This trial consists of a 12-week intervention and a 48-week follow-up period. Figure 1 shows the flow diagram of this study. This trial has been registered with the Chinese Clinical Trial Registry. Trial registration number: ChiCTR2200056239.
Participants
Inclusion Criteria
- Study participants must meet the diagnostic criteria of asthma in Global Initiative for Asthma.
(1)History of variable respiratory symptoms: Wheeze, shortness of breath, chest tightness and cough Descriptors may vary between cultures and by age.
(2) Confirmed variable expiratory airflow limitation, documented excessive variability in lung function (one or more of the tests below):
i: Positive bronchodilator (BD) reversibility test (more likely to be positive if BD medication is withheld before test: SABA ≥4 hours, LABA ≥15 hours): increase in FEV1 of >12% and >200 mL from baseline, 10-15 minutes after 200-400 mcg salbutamol (albuterol) or equivalent (greater confidence if increase is >15% and >400 mL);
ii: Excessive variability in twice-daily PEF over 2 weeks: average daily diurnal PEF variability >10%;
iii: Significant increase in lung function after 4 weeks of anti-inflammatory treatment: increase in FEV1 by >12% and >200 mL (or PEFby >20%) from baseline after 4 weeks of treatment, outside respiratory infections;
iiii: Positive exercise challenge test: fall in FEV1 of >10% and >200 mL from baseline;
iiiii: Positive bronchial challenge test (usually only performed in adults): Fall in FEV1 from baseline of ≥20% with standard doses of methacholine or histamine, or ≥15% with standardized hyperventilation, hypertonic saline or mannitol challenge;
iiiiii: Excessive variation in lung function between visits (good specificity but poor sensitivity): variation in FEV1 of >12% and >200 mL between visits, outside of respiratory infections.
2. Exposure to allergens (mainly dust mites, pollen, mold, and animal hair) can induce or aggravate symptoms, and an allergen skin prick test or serum sIgE test is positive for at least one allergen.
3. The participants must be in mild allergic asthma: controlled well by the Step 1 or 2 treatment.
(1) The Step 1 recommendations are for:
i: Initial asthma treatment in patients with symptoms less than twice a month and no exacerbation risk factors;
ii: Step-down treatment for patients whose asthma is well-controlled on Step 2 treatment.
(2) The step 2 recommendations are for: asthma treatment in patients with symptoms twice a month or more, but less than daily.
4. The participants must be between 18 and 75 years old.
5. The participant must sign informed consent forms.
Exclusion Criteria
- Patients with chronic obstructive pulmonary disease (COPD), bronchiectasis and allergic bronchopulmonary aspergillosis (ABPA).
- With a history of the ingredients of TMDCD allergies or being allergic to the budesonide-formoterol.
- Patients had received systematic allergen-specific immunotherapy within one year before enrollment.
- Patients with a malignant tumor, hematological disease, mental illness, or severe hepatorenal insufficiency.
- Pregnancy, ready to be pregnant or lactating patients.
- Unable to complete the tests, such as lung function, FeNO, blood routine, etc.
- Participate in other clinical studies at the same time.
Withdrawal Criteria
- Allergic asthma develops to moderate or severe level.
- Participants with poor drug compliance (<80% or >120% of the prescribed dosage) fail to complete the course of treatment specified or examination.
- Participants failed to abide by the relevant regulations and fill in the contents as instructed by the researchers.
- The blinding is uncovered or emergency unblinding is required, such as adverse events (AEs), or serious adverse events (SAEs).
- Lost the visit.
Participants Can Withdraw Voluntarily
Subjects have the right to withdraw from the trial at any stage, and they will not be punished or lose their welfare. The reasons for the subjects withdrawing should be recorded in the case report form (CRF).
Randomization, Allocation Concealment, and Blinding
The randomization of this study will be carried out according to block randomization. The 324 subjects will be randomly divided into intervention group (n=162) and control group (n =162) in a 1:1 ratio. Central Randomization System will be used to generate the randomized numbers. The study medications will be marked by pharmacists according to the random sequence. The random sequence will be stored in an opaque envelope and sealed subsequently. This trial is a double-blind clinical study. All researchers, participants, clinical research operators, drug and data administrators will be blinded to the grouping and medication of treatment. Placebo granules and TMDCD granules are similar in dosage form, appearance, size, color, taste, and smell. If participants experience an SAE need to be rescued urgently in the study, the principal investigators will carry out an unblinding. At the same time, the participant will be withdrawn from the study.
Intervention Method
The intervention group will be given TMDCD granules (one bag twice a day), and the control group will be given placebo granules. Treatment will continue for 12 weeks. During the treatment and follow-up period, all the participants will be allowed to use budesonide-formoterol (160μg of budesonide and 4.5μg of formoterol, produced by AstraZeneca, Sweden) and cetirizine hydrochloride tablets (10mg/ tablets, Yangzijiang Pharmaceutical Group Co., Ltd.) as needed. The subjects will be required to record the time, frequency, and dose of medication. If subjects inhale budesonide-formoterol more than 8 actuations over 24 hours, they still cannot escape from asthma symptoms. The subject will be terminated from the trial and receive emergency treatment.
TMDCD is composed of Prunus mume (Siebold) Siebold and Zucc (batch No.190728004), Cicadae Periostracum (batch No.900002134), Reynoutria multiflora(Thunb.) Moldenke (batch No. 90706003), Ganoderma lucidum (Leyss. ex Fr.) Karst. (batch No.001001212A), Saposhnikovia divaricata (Turcz. ex Ledeb.) Schischk (batch No.90917001), Gastrodia elata Blume (Orchidaceae) (batch No.20041302), Ephedra sinica Stapf (batch No.18090402), Prunus armeniaca L. (batch No.900021975), Gypsum Fibrosum (batch No.190724001), Glycyrrhiza uralensis Fisch. ex DC. (batch No.200352), Bombyx moriL. (batch No.180642), Fagopyrum cymosum(Trevir.) Meisn. (batch No.901001876).(Qin et al., 2021). The quality of TMDCD components complies with the general principles of the 2015 edition of the Chinese Pharmacopoeia. The primary content of the placebo is water, starch, dextrin, and bitterness. Besides, 5% TMDCD will be added to the placebo for the sake of having similarity with smell, color, and taste of TMDCD. TMDCD granules and placebo granules will be made by Beijing Kangrentang Pharmaceutical Co., Ltd. Figure 2 shows the enrollment, intervention, and evaluation schedule of this study.