Arthritis, Rheumatoid Clinical Trial
Official title:
Clinical Phase II Pilot Study of the Efficacy of FANG(30) to Treat Active Rheumatoid Arthritis in Adult Patients
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.
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.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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