Efficacy and safety of Tetramethylpyrazine (TMP) Phosphate on Pulmonary Hypertension: study protocol for a randomized controlled trial

Background: Tetramethylpyrazine (TMP), an active ingredient in the traditional Chinese herbal medicine Rhizoma Chuanxiong, has been used clinically for the prevention and treatment of cardiovascular disease. The benefits of TMP are largely attributed to its anti-oxidative and vasodilative properties. However, the efficacy of TMP in the treatment of pulmonary hypertension (PH) is unknown. We hypothesized that TMP may have a therapeutic effect in patients with PH. Methods: A randomized, single-blinded, clinical study with a TMP treatment group and a control group will be conducted to evaluate the efficacy and safety of TMP intervention in patients with PH. The recruitment target is 120 subjects meeting the following criteria: (i) At rest and at sea level, mean pulmonary artery pressure above 20 mmHg and pulmonary capillary wedge pressure below 15 mmHg; (ii) Type 1 or 4 PH in the stable phase; (iii) age 15–70 years; (iv) 6-minute walk distance between 100 and 450 meters; (v) lung function at level II, III, or IV according to WHO classification. Subjects will be assigned randomly into two groups at a ratio of 1:2 (control:TMP). Both groups will receive routine treatment, and the treatment group will also receive oral TMP (100 mg) three times a day for 16 weeks. All patients will be followed up for 4, 8, 12, and 16 weeks, and symptoms and patient compliance will be recorded. Discussion: We aim TMP


Background
Pulmonary hypertension (PH) is a serious condition characterized by sustained elevated mean pulmonary arterial pressure (mPAP) over 20 mmHg and the development of right heart hypertrophy, leading to cardiac failure and, ultimately, death. [1][2][3][4].With improvements in diagnostic techniques, PH is no longer a rare disease. According to the latest epidemiological data, the prevalence of PH is about 1% of the global population. [5] Although understanding of the pathophysiology and pathogenesis of PH has increased, and quality of life of patients has improved significantly through the use of targeted drugs, persistent high mortality rates indicate that these drugs delay the progression of the disease and alleviate symptoms but do not effectively prolong the life of the patients. [6][7][8][9] In addition, the use of effective drugs is limited by their high cost. Therefore, it is imperative to develop new and affordable medications with strong efficacy and safety profiles.

Study design
We designed a study protocol for a randomized controlled study. Screening (Visit 0) was undertaken within 3 days prior to enrollment to assess eligibility and collect baseline data.
Subjects who entered the primary screening were assessed for lung function, and those meeting all criteria were randomly assigned (2:1) into a TMP treatment group or a control group. Both groups received conventional treatment, and the TMP treatment group also received 100 mg oral TMP three times daily . Patients were followed up at 1 month after randomization (Visit 1), and then every month until end of treatment at 16 weeks. Data collected at Visit 0 included patient characteristics (name, sex, age), medical history, concomitant medications, laboratory and auxiliary examinations, and adverse events.
Additionally, at each visit, medical history, medications, cardiac and pulmonary function, and adverse events will be collected. Additional items will be evaluated at Visits 2 and 4. A schedule of assessments is shown in Table 1. A study flow chart is shown in Figure 1.

Sampling
Based on the 6-minute walk distance (6MWD) as the main efficacy index, it is assumed that after treatment, the experimental group has an average distance of 60 m from the control group of 6 minutes, the standard deviation is 60 m, α is 0.05, and the efficacy is 90% (β is 0.10). The sample size is: See supplemental files for the formula q1 is the proportion of the experimental group, and q2 is the proportion of the control group, q1=2/3, q2=1/3, N≈107.
Assume that the sample shedding rate is 11%, the sample size is approximately 120 participants, comprising 40 patients with control, 80 patients in TMP group.

Study procedure
Eligibility criteria for enrollment The selection of participants will be based on the following inclusion and exclusion criteria:  Clinical deterioration is defined as the need to increase medication or change the therapeutic regimen for the treatment of PH, particularly inhaled, intravenous, or subcutaneous application of prostacyclin and its analogues; aggravated symptoms of right heart failure that do not respond to diuretics; atrial septostomy or death; lung transplantation; or hospitalization caused by exacerbation of PH.
Other clinical symptoms and signs, biochemical indicators, and imaging indicators are 20 recorded (Table 2) for comprehensive prognostic evaluation and risk assessment.