Difficulty in recruiting eligible patients

This open label clinical study will be conducted in School of Chinese Medicine Clinics at The University of Hong Kong (HKU) to preliminarily determine whether treatment with the herbal formula PROLUNG could improve Idiopathic Pulmonary Fibrosis (IPF) symptoms, respiratory function and the quality of life of patients with IPF compared with pretreatment baseline. We propose to recruit 30 participants. The diagnosis and screening will be conducted by respiratory physicians. Those who meet the inclusion criteria will be referred by the expert to the PI. The PI will prescribe the formula in granule form to the participants in Traditional Chinese medicine (TCM) Clinics as usual. Patients will receive 6 months of the herbal treatment and 7 visits.

Annual rate of change in forced expiratory vital capacity (FVC) will serve the primary outcome. The St. George's Respiratory Questionnaire (SGRQ) will be used to additionally assess respiratory functions. A standard questionnaire will be administered to obtain information on age, sex, marital status, education, social class, smoking behaviour and respiratory diseases. Other outcome measures include the 36-Item Short Form Survey (SF-36) and the World Health Organization Quality of Life assessment instrument (WHOQOLBREF) by each participant after enrollment.

Background Idiopathic pulmonary fibrosis (IPF) is a dreadful disease characterized by progressive impairment in quality of life, increasingly limited physical function, and an early death from respiratory failure. IPF is the most common and predominantly lethal form of the idiopathic interstitial pneumonias, with an associated median survival of only 2 to 3 years. The etiology of this chronic and progressive fibrotic lung disease is unknown, although potential risk factors such as cigarette smoking and other environmental exposures have been described. In a study published in 2006 based on a United States healthcare claims database, the prevalence of IPF was between 14-42.7 per 100,000, depending on whether narrow or broad case-finding criteria was used. IPF is more commonly seen in patients between 40 to 70 years of age. The risk of death as a result of IPF also increases with age, with a hazard ratio of 0.25 for patients younger than 50 years and a longer median survival amongst those younger than 50 (116.4 months compared to 62.8 months). IPF occurs more commonly in men than in women and also progress faster and result in worse survival in men. The IPF mortality rate in the United States was found to be 61.2 deaths per 1,000,000 in men and 54.5 per 1,000,000 in women, nevertheless, the death rate in women is increasing at a faster rate than in men. Age-adjusted mortality has been found to be greater among whites than blacks and is increasing at a higher rate among whites when compared to other racial and ethnic groups. There is no effective treatment for IPF, although pirfenidone and nintedanib have been approved for treatment of IPF, with benefit in slowing down lung function decline. At present, the only intervention that improves survival in select patients with IPF is lung transplantation. With this to look forward to, it is no surprise that patients and their physicians are desperate for treatment options that might change the outcome. Traditional Chinese herbal medicine has been an important source to treat this ailment.

Traditional Chinese medicine (TCM) has dealt with IPF for long time. A condition similar to pulmonary fibrosis can be found in Chinese literature thousands years ago. A disease termed "Fei Wei" was described and is similar to IPF in definition, pathophysiology, and treatment. It was reported that the disease was extremely difficult to treat. Other TCM terms of respiratory disease similar to IPF were "short breath", "cough", "lung inflation", and "Fei Bi".

In recent years, TCM has renewed its focus on pulmonary fibrosis and other respiratory illnesses because of SARS (Severe Acute Respiratory Syndrome), a viral infection which spread in China in late 2002 and 2003. SARS infection resulted in pulmonary fibrosis in a number of individuals who contracted SARS, although the pathophysiology of pulmonary fibrosis resulting from SARS may differ from that of IPF, the fibrosis can be reversible. In TCM, the pathophysiology for IPF is a complex of group of terms: Feng (Wind-external factor), Re (Heat-inflammation), Tan (Phlegm), Yu (Congestion). Treatment may vary according to the phases of the disease, symptoms, and individuals.

IPF causes pulmonary interstitial chronic inflammation, immune complex deposition in the lung interstitium into fibroblasts and collagen eventually leads to the destruction of lung tissue. In TCM terms, this represents Blockage of Heat in the lung. With Heat in the pulmonary mass, the Lung loses the function of controlling Qi, hence the patients suffers difficulty in breathing, has no air suction, has shortness of breath, dry cough, wheezing, and other symptoms.

In China, herbal medicine is the main treatment for IPF. Research has shown the effectiveness of traditional Chinese herbs formulations developed to treat IPF. The Individual herbs of the formula have been widely used to improve pulmonary function.

Current evidence Chinese herbal medicine formula used in the proposed study

Our empirical evidence suggests that one Chinese herbal medicine formula PROLUNG has considerable benefit in the treatment of IPF. Individual herbs of the formula are listed as follows (weight in granule preparation):

Huang Qi (Radix Astragali Membranaceus): 2 g Dan Shen (Radix Salviae Miltiorrhizae): 1 g Jiang Huang (Rhizoma Curcumae Longae): 1 g Yin Xing (Semen Gingko Bilobae): 1 g Mai Men Dong (Tuber Ophiopogonis Japonoci): 1 g Bai He (Bulbus Lilii): 1g Jin Yin Hua (Flos Lonicerae Japonicae): 1 g Zi Su Ye (Folium Perillae Frutescentis): 1 g Yin Yang Huo (Herba Epimedii): 1g

The therapeutic effects in treating IPF: One study in animal model of IPF has shown that treatment with an herbal formula including Ginseng, Mai Men Dong, Tao Ren, Chi Shao, Neu Xi, Jie Geng, Dang Gui, Di Hung, Ban Xia, Gan Cao, Zhi Ke, and Hong Hua inhibited B cell hyperactivity, which may be related to fibrosis. IPF patients treated with a combination of traditional Chinese herbs and drugs improve faster and remain free of IPF longer than patients treated with drugs alone. One 2-month study was performed in 12 patients with IPF to find out the effect of a combination of Dang Shen, Huang Qi, Sha Shen, Mai Men Dong, Dang Gui, Dan Shen, Chuan Xiong, Sang Bei Pi, Xing Ren, Bai Guo, Huang Qin, Ban Xia, Ma Huang, and Gan Cao. The patients were exclusively provided with the Chinese herb formulation except when the illness worsened. The results have shown an improvement in dyspnea and cyanosis and an increase in PO2 (partial pressure of oxygen) in 5 of the 12 patients.

Dan Shen (Radix Salviae Miltiorrhizae): Dan Shen and its purified active component IH764-3, have been shown to prevent pulmonary fibrosis induced with bleomycin. The Chinese herb formulation blocks the expression of TGF-alpha1 and inhibits the activity of fibroblast growth factor when administered 24 hours after bleomycin-induction. Dan Shen has also been used successfully in the treatment of allergic rhinitis by bilateral injection into the inferior nasal choncha.

Huang Qi (Radix Astragali Membranaceus): Astragaloside is the main ingredient in Huang Qi, and is known to have antiinflammatory, anti-fibrotic, and immunoregulatory properties. It was reported to improve lung functions in mice experimentally induced chronic asthma by reducing the amount of hydroxyproline, an indicator of pulmonary fibrotic activity. The administration of Huang Qi in a population with history of bronchial asthma, allergic rhinitis, and chronic bronchitis, Huang Qi prevents against pulmonary tract infections. Among 30 patients with IPF treated with Huang Qi in combination with other Chinese herb formulations, 3.87% showed larger increase in diffusing capacity of the lung for carbon monoxide (DLCO) as compared with patients treated with prednisone in a clinical study. A combination of Huang Qi, Dan Shen and prednisone was given to 19 patients who had a 3.75% greater improvement in total lung capacity, a 4.01% greater improvement in vital capacity, and a 3.78% greater increase in DLCO than 19 other patients who exclusively received prednisone. Dan Shen and Huang Qi were components in an herbal combination that resulted in 3- and 5- year survival rates in subjects with IPF.

Jiang Huang (Rhizoma Curcumae Longae): Jiang Huang's anti-inflammatory properties have been established in rats. Curcumin, which is derived from Jiang Huang, also has anti-carcinogenic and antioxidant characteristics. Curcumin can limit the expression of tumor growth factor- β (TGF-β). It can also reduce TGF-β signaling in renal fibroblasts in vitro. It has been shown to limit hydroxyproline levels in the lungs of mice exposed to bleomycin and to prevent alveolitis in mice with bleomycin-induced IPF.

Yin Xing (Semen Gingko Bilobae): Yin Xing is recommended to treat chronic cough, asthma, chronic wheezing, phlegm, and chronic voice loss. The bronchodilation and expectorant properties of Yin Xing have been established.

Mai Men Dong (Tuber Ophiopogonis Japonoci): For chronic dry cough and sore throat, Mai Men Dong is a recommended treatment. Mai Men Dong in combination with other traditional Chinese herbs was shown to be effective in the treatment of allergic asthma in children.

Bai He (Bulbus Lilii): Bai He is recommended to be used in combination with other herbs, in the treatment of dry cough, bronchiectasis, and hemoptysis and alone in the treatment of lung abcesses.

Jin Yin Hua (Flos Lonicerae Japonicae): Jin Yin Hua is recommended to treat pneumonia, bronchitis, and upper respiratory tract infections in general in combination with other herbs.

Zi Su Ye (Folium Perillae Frutescentis): Zi Su Ye improves bronchodilation, decreases bronchioli excretions and relieves bronchiospasms.

Yin Yang Huo (Herba Epimedii): Yin Yang Huo has expectorant, antiasthmatic, and antitussive actions. Yin Yang Huo has shown effectiveness to treat chronic bronchitis.

Toxic profiles and herb interactions: Individual herbs used in the formula are in general safe and well tolerated within therapeutic doses. Dan Shen increased the effect of warfarin when the two medications are taken together. Dan Shen also increased the activity of liver enzymes involved in drug metabolism, thereby increasing drug metabolism rates. Jiang Huang may also exacerbate the effects of warfarin.

Inclusion Criteria:

• Either gender aged 40-75;
• Has a diagnosis of IPF, made by a respiratory expert based on International Classification of Diseases (ICD-10);
• No participation in another clinical study within 4 weeks of study start.
• Participation in this study must be voluntary and not coerced.

Exclusion Criteria:

• Have received lung transplantation.
• Any condition that may compromise patient safety.
• Pregnant women or women trying to become pregnant will be excluded from the study.
• History of drug or alcohol abuse within 6 months of study start.
• History of immunocompromise, including a positive HIV test result.
• Impaired liver and renal functions.
• Known allergies to any Chinese herbs and participants with numerous or severe allergies to any allergen.
• Pre-existing conditions including renal failure, chronic renal problems, chronic hepatitis, other pulmonary problems, diabetes, and heart problems will be excluded from the study.
• Either mentally incompetent or are unable to give informed consent because of the language barrier.
• Taking the following drugs, even as part of their current treatment regimen for IPF: pirfenidone, nintedanib, antiplatelet drugs (including aspirin, clopidogrel (Plavix), and dipyridamole (Persantine), anticoagulant drugs (including warfarin (Coumadin), enoxparin (Lovenox), and heparin), cardiac glycosides (e.g. digoxin), sedatives and sedative-containing drugs (including barbiturates, narcotic analgesics, benzodiazepines, and antihistamines), and traditional Chinese herbal medicines or granules, or other herbal medicines or supplements.