Men and women between the ages of 18 and 80 years were enlisted if they had knee trauma or overuse of the knees prior to the onset of symptomatic osteoarthritis. Only uncomplicated hypertensive patients solely on Nifedipine were included. Within the routine clinical practice, many of our confirmed KOA patients do present with hypertensive heart disease on multiple therapies. Basically our research center is in resource constrained country where high technology laboratory support needed to identify specific adverse drug interactions that could be associated with multiple anti hypertensive medications is not available. It was due to this peculiar limitation and the need to enhance clarity of interpretation of subject's clinical features, study drug's efficacy and safety assessment within available international standard facilities that necessitated the inclusion of patients with uncomplicated hypertensive solely on Nifedipine.
Patient's diets were not altered from their pre study period. The other inclusion criteria in the study were – osteoarthritis of the knee verified according to the clinical, laboratory, radiographic criteria of the American College of Rheumatology (ACR) and resting visual analog scale pain intensity in the target knee > 45 mm.
Patients with known allergic reactions (to Garcinia kola, celebrex and naproxen); Kidney failure (blood creatinine > 84 umol/L); abnormal liver function (SGOT > 35 U/L or SGPT > 35 U/L or GGT > 50 U/L); gastrointestinal ulcers (bleeding or discolored stool during the past 8 weeks); malignant diseases; systemic therapy with corticosteroids during the past 8 weeks; surgery of the test joint during the past 8 weeks; inflammatory joint diseases(ESR > 40 mm/h);chronic heart failure (NYHA grade III or IV); Chronic obstructive airway disease requiring prophylactic medication and participation on a clinical trial during the past 4 weeks. Patients with absolute indication for surgery and knee instability were excluded. Subjects with high levels of clinical disability (> 34 on the WOMAC scale) were excluded as it was unlikely that they could perform the experimental protocol consistently. Also the knee requiring no weight bearing and who had intra-articular injections into the study joint within 3 months prior to first visit were excluded. No herbal or allopathic treatment, which could influence the outcome of the study, was permitted during the course of the study. Crossing over of patients from one subgroup to another was excluded through surveillance.
Subjects were recruited into the study between February 20th, 2004 and August 19th, 2006 at the orthopedics and general outpatient's clinics of the Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife (OAUTHC); Nigeria.
Study medication and blinding
At the beginning of the study, no commercial preparation of Garcinia kola was available. G. kola seeds were obtained from a market in Ile-Ife, authenticated by Mr. A.T. Oladele, the herbarium, Department of Pharmacognosy, Obafemi Awolowo University.
G. kola 200 mg was given twice orally per day for six weeks. Active comparators were Naproxen 500 mg tablets twice daily, and Celebrex 200 mg twice daily were given orally. Placebo study medication was ascorbic acid, 100 mg tablet given twice daily. The patient in each group was given identical study medication of the same physical appearance aimed at eliminating psychological effects on the subjects. The subjects have not been previously exposed to research drug medications.
All study medications were prepared by a 10 years post-qualified nursing staff and administered to each patient by a senior registrar in orthopedic surgery. A family medicine physician of five year post fellowship qualification acted as a masked clinical outcome evaluator. The voluntary nursing staff, the senior registrar and masked evaluator were not part of the study group. The Nifedipine for hypertensive were supplied to patients from the teaching hospital pharmacy shop to ensure uniformity of quality control. A consultant radiologist with a neutral role status in the study screened the plain X-ray of patients and confirmed radiological features of knee osteoarthritis.
It was a randomized, double-blind, placebo-controlled, parallel-group study trial of the clinical effects of G. kola in knee osteoarthritis. The research medication dose assessor, clinical assessors, subjects and orthopedic surgeons were blinded to the treatment group for the six weeks of study. The G. kola subgroup was followed up for the midterm evaluation of therapeutic effect after the intake was discontinued.
The study was approved by the institutional medical ethics review board and was carried out in accordance with the ethical principles of the Declaration of Helsinki. A written informed consent was obtained from each patient that fulfilled the inclusion criteria before randomization.
To determine the presence of KOA, detailed history was obtained and clinical examination performed. Adults were classified as having clinical knee OA by using the criteria determined by the American College of Rheumatology (ACR) .
Randomization occurred in blocks of four within each stratum, using computer generated random numbers (Excel 5.0). The patients were grouped into four (A = placebo, B = naproxen, C = Garcinia kola, D = celebrex). Both assessors and patients were blind to the allocation and not informed about the block size until after completion of the study. Subjects were treated for six weeks and each of them had weekly follow-up visits until the time of study withdrawal. Study medications were taken in the morning and at noon, half an hour before meal times. No additional analgesics, NSAIDs or systemic corticosteroids were allowed during the study phases.
At all visits, the patients completed WOMAC index to assess pain, stiffness, and physical function. The primary efficacy end point was the mean change from baseline in the WOMAC pain subscale VAS at six weeks. Secondary outcome measures included the stiffness and physical function.
Patients were assessed by consultant orthopedic surgeon at days -7, 0, 7, 14, 21, 28, 35 and 42.
The initial assessment (day -7) comprised of medical history, examination and WOMAC-VAS index. The "most painful knee joint" refer to the side of knee joint with the highest VAS pain score when a subject is having bilateral KOA. In bilateral knee OA, the side of the knee joint with the highest VAS pain score was the primary focus of measurement for future assessment in the study. Blood and urine samples were taken for standard laboratory tests. The onset of therapeutic effect of the study medication as used in this study was the mean time (minutes) recorded for the onset of KOA symptomatic reliefs. The duration of therapeutic effect of the study medication was the mean time (minutes) recorded for the return of KOA symptoms after a relief following study medication intake.
The radio diagnostic criterion of Kellgren and Lawrence scheme was used for the knee osteoarthritis severity assessment. All patients underwent radiographic analysis of both knee joint using Kellgren-Lawrence less or equal to grade 2 as case definition.
The level of clinical disability was quantified by using the Western Ontario and McMaster University Osteoarthritis (WOMAC) index . Disability was assessed using the physical function section of WOMAC, which contains 17 questions relating to functional disability, scored from 0 to 4 by the subject.
At the second study visits (day 0), laboratory findings were compared with exclusion criteria and diary entries were checked. Patients who met all study criteria filled in the WOMAC questionnaire (baseline), received study medication and thereby entered the intent to treat population.
At the study visits on days 7,14,28,35, and 42, patients filled in WOMAC questionnaires, and compliance was checked by diary entries and study medication. Adverse events were recorded by checking diary entries as well as by direct questioning of the patients.
At the study visit on day 42, blood and urine samples were taken. The masked clinical outcome evaluator and consultant orthopedic surgeon independently recorded their final overall assessment of the change of disease activity by the study medication on 100 mm visual analogue scales (VAS). Direct inquiry and visual inspection of the returned sachets container were used for monitoring compliance. The osteoarthritis protocol instrument used for the study has a section on the disease symptom/symptom description. It evaluates each subject from the day 0 to the end of study at six weeks. The subjective response of the patients to the questions on walking distance was distinct. They were asked if the distance used to cover by walking has improved, or there is no change, or it deteriorated at the end of the study compared to the day 0.
The subjects who had received at least a dose of the research medication s were assessed for their safety. Tolerability evaluations consisted of determining clinical laboratory test abnormalities such as hepatic (aminotransferase activities) and renal (serum creatinine) function, adverse events, and physical examinations. Adverse events reported by the patient or observed by the investigator during clinical evaluation were recorded. In addition, patients were questioned at each visit regarding the occurrence of adverse events using a nonspecific question. Investigators rated the intensity of adverse events and their subjective assessment of the relationship to study medication while blinded to the treatment group.
All analyses were performed on the intention to treat cohort, defined as all patients who took at least a dose of study medications. Data were analyzed by using Statistic Package for Social Sciences (SPSS) version 11.0 for windows. The comparability of patients in the four treatment groups was determined from the demographic data and baseline haemodynamic values. The change in the mean of the group and mean time of study medications therapeutic duration were evaluated using 2-way ANOVA with Post Hoc comparison test. The confidence interval (CI) was at 95% and the P-value was considered significant at p ≤ 0.05.
Limited numbers of knee osteoarthritis patients were available for the study. Lack of research grants to provide study medications and laboratory investigations free for long term and to include larger groups of would be subjects at multiple centers in Nigeria.