Efficacy Study of FANG(30) for Active Rheumatoid Arthritis in Adult Patients
Condition: Arthritis, Rheumatoid
MeSH terms: Arthritis; Arthritis, Rheumatoid
Study type: Interventional
Phase: Phase 2

Summary: 
      This is a Clinical Pilot Phase II interventional, double blind, randomized and placebo
      controlled study to document the efficacy, tolerability and safety of FANG(30) in 60 adult
      patients affected with active Rheumatoid Arthritis. Also, to evaluate the effect of an
      andrographolide natural formula, identified as FANG(30) or "the study product", on the
      immunological functions that influence chronic inflammatory process in these patients, who
      could benefit with this treatment.
    

Detailed description: 
      Introduction: Rheumatoid Arthritis (RA) is a common rheumatic disease characterized by pain,
      inflammation and reduction in joint function. Hands and feet are the most commonly affected
      joints and pain is the cause that brings patients with RA to search for medical assistance.
      Factors causing pain and the risk of physical incapacity are still poorly understood. Joint
      pain in RA is, generally, a profound pain, focalized in the involved joint. Typically, pain
      increases when joint moves and decreases when joint is at rest. But, in the advanced form of
      the disease, pain can be persistent and some patients can feel night pain, or rigidity and
      pain after a period of inactivity, that last more than 1 hour and decreases when some
      activity is taken up again, i.e. rigidity and early morning pain. Clinically, these patients
      present with symptoms such as localized sensibility on the joints, and slight edema of the
      tissue, bone crepitating and heat on the outer joint. Muscular atrophy with or without
      muscular spasm can be seen. In the advanced form of the disease, there is deformity and
      complete loss of joint movement. Analgesic drugs, specially the non steroidal
      anti-inflammatory drugs NSAIDs play an essential role in the management of RA. These drugs
      are not only effective in the rapid and sustained relief of pain, but at the same time they
      can have an acceptable profile of safety and tolerability in medium and long term treatment.
      However, there are cases of gastric intolerance and /or renal or hepatic dysfunction. The
      anti-inflammatory effect of non steroidal anti-inflammatory drugs NSAIDs, is mainly due to
      the inhibition of the cyclooxygenase enzyme (COX), that is needed for the synthesis of
      prostaglandins and thromboxanes.

      Description of FANG used in this clinical trial: FANG(30) is a product manufactured by
      FARMINDUSTRIA S.A., Pharmaceutical Laboratories, Santiago, Chile, in the form of a common
      medicine, according to Good Manufacturing Practices (GMP) Guidelines & Requirements of the
      Institute of Public Health of Chile (ISP), from a standardized and patented extract of A.
      paniculata, Nees (Acanthaceae), a medicinal plant native to India and China. Its chemical
      composition and principal active compounds are bitter diterpenic lactones, specially
      andrographolide, deoxy-andrographolide and neoandrographolide, in tablets weighting 100 mg
      with a 30 % of the active principle. This plant is vastly distributed in the countries of
      Southeast Asia and has been used as an official medicinal plant in China and India for
      thousands of years. It still continues as a popular medicine for the treatment of different
      diseases. Recently it has been demonstrated to possess anti tumoral5, anti-inflammatory6 and
      antiviral7 effects. Andrographolide is particularly efficient in regulating the immune
      response 5, 7. The molecular and cellular mechanisms responsible for the immunomodulating and
      anti-inflammatory properties of andrographolide, remain still unknown, however, recent in
      vitro and in vivo studies, indicate that andrographolide inhibits NFkappaB8. Specifically,
      andrographolide in concentrations of 10 µM interferes with the DNA binding of NF-κB reducing
      the expression of COX-2 in neutrophils induced with fMLP and PAF. Moreover, andrographolide
      reduces the production of IFNγ and IL-2 in T cells stimulated with CON-A, without affecting
      the cellular viability or inducing apoptosis. Also the apoptosis induced by corticosteroids
      in thymocytes was reduced. Andrographolide and 14-deoxyandrographolide are able to inhibit
      the ERK1/2 phosphorylation in T cells and neutrophils, respectively 9, 10. In inflammatory
      processes, FANG has shown potent anti-inflammatory effects, reducing the production of
      cytokines, derived from phospholipids, nitric oxide and reactive oxygen species that are the
      "fuel" for chronic inflammation, explaining its capacity to reduce and control inflammation,
      inflammatory pain and facilitate the induction of cellular repair. Clinical Evidence of some
      effects of A. paniculata: During the last decades, A. paniculata has become popular in
      Scandinavia for the treatment of common cold. Accumulated evidence indicates that it can
      reduce the severity of this disease. Various clinical studies indicate that A. paniculata is
      effective for the treatment of viral infections of the upper respiratory tract. A
      meta-analysis in 2004 on 7 double blind controlled clinical trials that met the criteria and
      scientific quality accepted for this meta design, including 896 participants, which evaluated
      the efficacy of A. paniculata for the treatment of acute respiratory infections11, indicates
      in the combined results, that A. paniculata was more effective than the placebo in reducing
      the symptoms of common cold. A. paniculata has also been compared to acetaminophen. In a
      double blind randomized study with 152 patients with fever and pharyngeal congestion 12 high
      doses of A. paniculata (6 g) reduced fever and sore throat in a similar manner to
      acetaminophen, without significant secondary effects. In a double blind randomized trial,
      against a placebo, with 107 patients, A. paniculata increased resistance to common cold 13,
      reducing the incidence of colds by a factor of 2.1 times compared to the control group after
      a 3 months treatment during winter season. Safety Parameters - Toxicity and Tolerability of
      FANG: Acute and sub-chronic toxicity in rodents and pigs using an extract of A. paniculata
      the component of FANG, performed at the Institute of Pharmacology and Toxicology, Universidad
      Austral de Chile according to Good Laboratory Practice (GLP) and Food Administration Agency
      (FDA), showed the absence of adverse effects with doses >20g/kg after 90 days of treatment.
      Not genetic, or reproductive, immunological, neurological, hematological, metabolic,
      histopathological toxicity were detected either. Also, in a Phase I clinical trial, where the
      participants were monitored for liver, renal and hematological parameters, no clinical or
      laboratory secondary effects were described 11, 13, 15. Bio safety studies in small children,
      nursing mothers, patients with renal or hepatic damage have not been performed yet. On the
      other hand, since A. paniculata can stimulate the contractibility of gall bladder. Therefore,
      it should not be used without medical supervision or in patients with gall bladder pathology.

      Objective of Study: To assess and measure the anti inflammatory efficacy of this test natural
      product and contribute learning about some of the basic biological mechanisms by which
      produces its effects, on adult patients with active Rheumatoid Arthritis. Methodology: For
      this purpose, there will be 2 groups of patients who will respectively receive at random, an
      either inert substance known as placebo, and the other group that will receive the test
      product in the form of coated tablets, three times every day, during the period of study that
      will last 14 weeks.

      Place of Study: National study in Chile with 2 centers, one in the city of Valdivia and one
      in the city of Osorno with a number of 30 patients per centre and enrolled by their
      respective rheumatologists. Population of Study: 60 adult individuals of both sexes diagnosed
      with Active Rheumatoid Arthritis and undergoing standard treatment will be included.
      Individuals with chronic or acute disease, smokers, alcoholics, diabetics, heart diseases,
      lung diseases, neoplastic diseases, and individuals taken any other medicine will be
      excluded. Product of Study: The experimental FANG (30) and the placebo tablets were
      manufactured and stored as specified, and will be delivered and administered as proposed in
      this protocol. Procedure: A total of approximately 30 individuals will be assigned to the
      placebo group, and 30 to the FANG(30) group. During 14 weeks, each of them will daily take 3
      tablets of the respective randomly assigned product. All volunteers will allow obtaining a
      monthly blood sample by simple venipuncture from the superior arm at day 0, 30, 60, 90 and
      120 days of treatment.

      Discomfort and derived risks of the study: Since the participants, will need to take tablets
      of the product 3 times a day and submitted to the extraction of 4 blood samples during the
      study period, these facts can represent in some cases, a physical and emotional discomfort,
      depending of the customs and individual predisposition for this type of common medical
      procedures. Adverse Effects: Andrographis paniculata extract is not toxic and the
      manufactured product FANG(30) is prepared under GMP with pharmaceutical quality as requested
      for this study. The product is well tolerated and no complications are reported in the vast
      available information. However, as any natural and / or pharmaceutical product, in isolated
      cases, there can be slight risks such as rushes, allergies to the active principles of the
      plant, which anyhow, are reversible with the suspension of the intake of the product.
      Moreover, if in one of the patients, an alteration is detected that could be dangerous or
      inconvenient for his or her health condition; physicians will offer this patient to withdraw
      from the study. In case of a severe alteration, the rheumatologist will withdraw the patient
      from the study for safety reasons.

      Principal expected results: At the end of the study period, participants receiving the active
      product FANG (30) (Andrographis extract tablets), should show an improvement in their
      symptoms. Moreover, participants that received placebo should not show any sign of change in
      their symptoms. Any situation of health detected during the course of the study, related to
      the analyzed parameters, or any other aspects of clinical significance, even not necessarily
      included in this study, will be duly recorded and informed accordingly. If end results
      demonstrate that FANG(30) in a particular case has proven to be beneficial, all participating
      patients (even those having received a placebo) will be offered by their rheumatologists a
      free treatment with this same medicine in a regular modality, for the next 18 months.

      Volunteering: Volunteers must be absolutely free to apply and participate, in order to be
      included in this study, as for no reason whatsoever nobody can oblige a person to participate
      under any condition or threat. Moreover, volunteers can abandon and not continue
      participating in this study at any moment and without necessity of given explanations. This
      event will not affect the relationships with treating physicians, neither with the personnel
      of the hospital, or have any relation or influence with volunteer's future health care
      requirements. Volunteers can, and must consult all doubts about the study in which they have
      been invited to participate, before accepting and also during development of the study.
      Insurance for the Study: Considering the previous experience with the drug, of being of free
      sale in other countries; being approved by the Institute of Public Health in Chile,
      authorized to be sold as a nutraceutical in the USA, no hiring of specific insurance for
      special risks of this study has been considered. Moreover, this study has no special funds
      for the payment of compensations for damages resulting from adverse effects to the test
      medicine. Nevertheless, in case some event of this nature would happen, volunteers will be
      assisted with all the procedures and therapies they require, and continue to be monitored by
      a study physician for their care. In case of additional interventions needed, but not derived
      directly from adverse effects of this study and not covered by regular health insurance
      systems, these events will be also covered by the insurance policy of this study. This
      insurance policy will be maintained current for up to 4 months after the completion of the
      study. Responsible rheumatologists to inform volunteers on the study, to clarify doubts or
      answering questions are Dr. Verónica I. Aguirre at Hospital de Valdivia and Dr. Sonia M.
      Arriagada at Hospital de Osorno.
    

Intervention name(s): FANG(30); Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Andrographolide formula Oral tablets, 30mg, three times per day, during a total of 105 continuous days.; Placebo 30mg tabs, 3/day, 105 days continuously.
Other intervention name(s): FANG 30mg tablets, FARMINDUSTRIA, Lots FANG06 & 01-ANDRO-07; FARMINDUSTRIA Specific Placebo tabs/Lot FANG06 & 01-ANDRO-07
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Arthritis, Rheumatoid, Andrographolides treatment, Efficacy.