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HUMAN CLINICAL TRIALS

HUMAN CLINICAL TRIALS

A total of ten human clinical trials have been conducted on BCM-95 and reported in thirteen publications. Six publications involve the category of mental and cognitive health: Three clinical studies explored the benefits for major depression, and an additional publication explored the potential mechanism of action. A fourth trial investigated whether BCM-95 might prevent cognitive decline associated with old age, and a fifth trial investigated the potential benefit to patients with Alzheimer’s disease. The study with patients with dementia also investigated the effect of BCM-95 on serum lipid levels. Two additional human studies with BCM-95 are in the category of joint health — one on osteoarthritis (OA) and the other on rheumatoid arthritis (RA).

Two trials explored chemopreventive benefits, evaluating the effects of BCM-95 in patients with oral submucous fibrosis, and oral leukoplakia, chronic precancerous condition of the mouth.

Finally, the last study investigated urinary, sexual, and bowel function, and antioxidant status in patients undergoing radiation therapy for prostate cancer.

Mental & Cognitive Health

Sanmukhani et al., 2014 — Major Depression

A randomized, observer-masked (single-blind), three-arm, parallel study was conducted comparing BCM (500 mg twice daily) to fluoxetine (20 mg/day) and the combination of the two treatments given to patients with major depressive disorder (MDD) for six weeks.27 The patients were men and women with a mean age of approximately 37 years, diagnosed with MDD according to criteria in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th ed. The primary variable was the Hamilton Depression Rating Scale, 17-item version (HAM-D17), measured before and after two, four, and six weeks of treatment. There was no placebo control for ethical reasons. The study began with 60 patients, 20 in each of the three groups. Overall, 45 patients completed the study with no significant difference in the dropout rate for each group. The “intention-to-treat” proportion of responders was highest in the group taking both BCM-95 and fluoxetine (77.8%), compared to the fluoxetine group (64.7%) and the BCM-95 group (62.5%). However, there were no statistically significant differences among groups. The secondary outcome measures — mean change in HAM-D17 scores and remission rate according to the HAM-D17 — also were similar for the three groups. There were also no significant differences among the three groups in global efficacy as assessed by the investigators (P = 0.66). The percentage of patients with ‘excellent’ or ‘good’ response to the study medication were 70.5% [46.8 – 86.7] in the fluoxetine group, 75% [50.5 – 89.8] in the curcumin group, and 83.3% [60.7– 94.1] in the fluoxetine and curcumin group.

Turmeric Curcuma longa
Photo ©2019 Steven Foster

 

All treatments were administered without effects on vital signs, laboratory tests, or electrocardiograms. The reported adverse effects were mild, with the most common being gastritis in all three groups.

Lopresti et al., 2014 & 2015 — Major Depression

In an eight-week, randomized, double-blind, placebo-controlled study, 52 men and women (18 to 65 years old) with MDD were treated with BCM-95 (500 mg twice daily) or placebo.28 BCM-95 and placebo were provided by Arjuna Natural Extracts Ltd. The primary measure was the Inventory of Depressive Symptomatology self-rated version (IDS-SR30). Secondary outcomes included the IDS-SR30 factor scores and the Spielberger State-Trait Anxiety Inventory (STAI) score.

From baseline to week four, both BCM-95 and placebo were associated with improvements in the IDS-SR30 total score and most secondary outcome measures. From weeks four to eight, BCM-95 was significantly more effective than placebo in improving several mood-related symptoms, demonstrated by a significant group × time interaction for IDS-SR30 total score (P = 0.045) and IDS-SR30 mood score (P = 0.014), but none for IDS-SR30 arousal score. Both BCM-95 and placebo groups showed a reduction in STAI scores (state and trait anxiety). There were no significant “group × time” interactions across the full eight weeks of treatment for either STAI score. However, there was a trend towards a reduction in the STAI trait score from week four to week eight (P = 0.097). The authors indicated that the data suggested that depression in both groups improved for the first four weeks and after that, improvement continued in the curcumin group, while the placebo group remained static. Items in the IDS-SR30 have been used to categorize patients into categories of atypical or melancholic depression. Greater efficacy from curcumin treatment was identified in a subgroup of individuals with atypical depression.

The same research group published a secondary, exploratory analysis of salivary, urinary, and blood biomarkers collected during the above study in order to identify potential antidepressant mechanisms of action for curcumin.71 Pre- and post-intervention samples were provided by 50 patients. Compared to placebo, eight weeks of BCM-95 supplementation was associated with elevations in urinary thromboxane B٢ (P < ٠.٠٥) and substance P (P < ٠.٠٠١). In the placebo group, there were reductions in aldosterone (P < ٠.٠٥) and cortisol (P < ٠.٠٥). There were no significant changes to biomarkers in plasma or saliva. Further examination of the data for correlations between the IDS-SR30 total score and levels of biomarkers indicated an apparent relationship between high levels of plasma endothelin-1 at baseline (> 1.47 pg/mL) and greater reductions in the IDS-SR30 score after eight weeks of curcumin compared to placebo. However, the change in the IDS-SR30 score was not accompanied by a decrease in the level of this marker. No changes in urinary biomarkers were related to treatment outcome. The authors of the study commented that these findings should be interpreted cautiously as multiple statistical analyses were completed, increasing the risk of type I errors (detecting an effect that is not present).

Lopresti and Drummond, 2017 — Major Depression

The clinical trial on MDD reported by Lopresti and colleagues, described above, was followed by another study that explored whether half the usual dose of BCM-95 would be as effective against MDD, and whether combining the lower dose of BCM-95 with a saffron extract would have an additive effect in treating depression and anxiety.32 The study was randomized, double-blind, and placebo-controlled, and had a 12-week treatment period and one-week placebo “run-in” phase. The participants were 111 men and women (18 to 65 years old) with MDD who were divided into four groups: (1) 500 mg BCM-95 twice daily, (2) 250 mg BCM-95 twice daily, (3) 250 mg BCM-95 plus 15 mg saffron extract twice daily, or (4) placebo. The saffron extract was prepared from the stigmas of Crocus sativus (Iridaceae) and characterized as containing a minimum of 3.5% lepticrosalides including safranal and crocin. All interventions were provided by Dolcas-Biotech LLT of Landing, New Jersey. As in the previous study, the primary measure was the IDS-SR30, and the secondary outcome measure was the STAI score. Over 12 weeks, the IDS scores were significantly reduced in all groups, although in the placebo group that decrease was limited to the first four weeks of treatment. Results from all of the active groups combined, compared to results from the placebo group, produced a significant “time x group” interaction from baseline to week 12 (P = 0.031). There were no significant differences in “time x group” analysis between the three active treatments. The IDS response rate for the combined active treatments was 28%, which was twice the 13% response rate for the placebo group, but the difference did not reach statistical significance (P = 0.074). The combined active treatment groups also showed significantly greater improvements in STAI-state (STAI-S) and STAI-trait (STAI-T) scores over 12 weeks, compared to the placebo group.Again, comparisons between the active groups did not show any significant differences. As in the previous clinical trial, the active treatments were more effective for participants diagnosed with atypical depression compared to the other depressed participants (IDS, P = 0.007; STAI-S, P < 0.001; STAI-T, P = 0.009). The response rate for a subgroup with atypical depression (65%) was significantly greater than the overall response rate (35%; P = 0.012). The authors concluded that the results of the present study provide additional support for the use of BCM-95 for anxiety and depression (particularly atypical depression), with no significant differences in efficacy between the doses of 500 mg and 1000 mg per day. The addition of the saffron extract did not enhance efficacy. This study also supported the idea that BCM-95 might help those with atypical depression more often than those with other categories of depression.

Rainey-Smith et al., 2016 — Cognitive Health in Older Adults

A 12-month randomized, double-blind, placebo-controlled study examined the ability of BCM-95 to prevent cognitive decline in a population of healthy older adults 33 Participants were randomly assigned to take either 500 mg three times daily of BCM-95 or matching placebo capsules containing roasted rice powder. The Montreal Cognitive Assessment (MoCA), the Rey Auditory Verbal Learning Test, the Controlled Oral Word Association Test, the Wechsler Digit Symbol Scale from the Wechsler Adult Intelligence Scale, and the CogState battery were administered to patients at baseline, six months, and 12 months. Initially, 160 community-dwelling adults (40 to 90 years old) without significant cognitive impairment were enrolled into the study (80 in each group). The final analysis included 57 patients in the placebo group and 39 patients in the treatment group. There were no differences between groups in cognitive performance from baseline to 12 months. At baseline, the placebo group performed significantly better than the treatment group in the MoCA; at six-months the comparison was reversed, and at 12-months there was no difference between the groups. A significant “time ×treatment” group interaction for MoCA was produced for baseline, six-month, and 12-month data but not when the six-month data was excluded. The authors concluded that the 12-month study did not show a significant effect for BCM-95 on cognitive function, mood, or general quality of life. The participants In the study were cognitively healthy and did not show much decline over the year. The authors speculated that there might not have been sufficient magnitude of change to detect an improvement due to BCM-95. Further studies with larger numbers of participants over longer periods of time may be required to measure the ability of BCM-95 to slow cognitive decline.

Baum et al., 2008 — Alzheimer’s Disease

A six-month, randomized, double-blind, placebo-controlled, pilot clinical study explored the effects of two doses of curcumin compared to placebo in patients with probable or possible Alzheimer’s disease according to NINCDS-ADRDA.30*** The study included 31 male and female patients over 50 years old with a progressive decline in memory and cognitive function over the previous six months. Patients were randomly assigned to receive 1 g curcumin, 4 g curcumin, or placebo. As the volume of curcumin was large and thought to be inconvenient, the patients were allowed to choose between taking 10 capsules containing BCM-95 after a meal or packets of curcumin powder (not BCM-95) to be mixed with food. The packets of powder (n = 12) were provided by Kancor Ingredients Ltd. (The forms of curcumin were not the same.) The placebo was yellow starch. All patients received a capsule containing 120 mg standardized ginkgo (Ginkgo biloba, Ginkgoaceae) leaf extract (Shanghai Charoma; Shanghai, China; no further description of the ginkgo extract was provided). Patients were also allowed any additional treatment deemed appropriate by their physicians. Plasma samples were obtained at baseline, one month, and six months and assayed for isoprostanes, antioxidants, and amyloid beta-40. Cognition was assessed using the Mini-Mental State Examination (MMSE) at baseline and six months.

Thirty-four male and female patients began the study, and 27 completed it (dropout rate: 20%). The seven dropouts were due to gastrointestinal complaints (n = 3), complications due to falls (n = 3), and respiratory tract infection (n = 1). The final compositions of the groups were as follows: 1-g group (n = 8; one man and seven women), 4-g group (n = 11; three men and eight women), and placebo group (n = 8; three men and five women).

There was no change in cognition due to curcumin at either dose compared to the control group, as measured using the MMSE scores. Serum levels of amyloid beta-40 did not differ significantly among groups. There was a tendency towards an increase in the 4-g group but this did not reach significance. There were no significant changes in plasma levels of isoprostanes. Serum levels of vitamin E increased for those taking the curcumin capsules (BCM-95) but decreased for those taking powdered curcumin and for those in the placebo group. The change in vitamin E levels correlated with the level of total curcuminoids in plasma.

In summary, this study did not demonstrate an improvement in cognitive abilities due to either form of curcumin. The patients in the placebo group did not have a decline in their cognitive abilities and this may have precluded observing any benefit due to curcumin. A weakness of the study design was that all patients were taking a standardized ginkgo extract; a proprietary ginkgo extract from Germany has demonstrated the ability to improve cognition for patients with early stages of Alzheimer’s disease in several clinical studies (although, as noted above, the Chinese ginkgo extract used in this study was not adequately described to be able to determine if it was chemically similar to the German extract). Suggested mechanisms for benefits to patients with Alzheimer’s disease include disaggregation of amyloid-beta plaques, and anti-inflammatory and antioxidant activity. Ginkgo extracts have demonstrated antioxidant and anti-inflammatory properties, so any changes in these parameters due to curcumin would have to be beyond that due to ginkgo. Another complication of the study was the difference in the form, and perhaps content, of the two curcumin preparations. In summary, no difference was observed among the groups in the Alzheimer’s parameters tested.

Cardiovascular Health

Baum et al., 2007 — Blood Lipids

In a report of additional measurements conducted during the 2008 Baum et al. study described above, plasma lipids were measured.31 Plasma samples were obtained at baseline, one month, and six months and assayed for cholesterol (total, high-density lipoprotein [HDL], and low-density lipoprotein [LDL]) and triacylglycerol. There were no significant between-group differences in these parameters at any of the time points. A complication of this study, as discussed above, was that the patients all took an undefined ginkgo extract and other undisclosed treatments for Alzheimer’s disease. In addition, it might have been more likely to observe an effect on cholesterol levels if the study patients had a pre-existing condition of hypercholesterolemia or were fed a high-fat diet.

Joint Health

Antony et al., 2011 — Osteoarthritis

A randomized, two-arm, open, 12-week study†††compared the effects of Rhulief® (500 mg twice daily) to celecoxib (100 mg twice daily) for treatment of OA of the knee.72 Rhulief 500-mg capsules (produced by Arjuna Natural Extracts, Ltd.) contained BCM-95 (350 mg) and BosPure (150 mg B. serrata extract standardized to 10% 3-O-acetyl-11-keto-b-boswellic acid). The patients were 18 to 65 years old, with moderate OA of the knee characterized as narrowing of the medial joint space with swelling. Patients with more severe OA with gross radiological damage to joints and restricted mobility were excluded. Fifty-four patients were screened, 30 enrolled, and 28 completed the study. Both groups showed improvement in joint pain, which decreased for most patients from moderate pain to mild pain. While there was a trend towards a greater reduction in the Rhulief group, there was no significant difference between groups. Both groups exhibited a significant increase in the number of patients able to walk 1,000 m without limiting pain. Significant improvements were also observed in crepitus and range of motion in both groups. Measurements of joint swelling, warmth of joint, gait, and thigh were not changed by either test agent. There were no safety issues, as monitored using vital signs (blood pressure, pulse, and respiration), hematological parameters, liver enzymes, and renal function parameters. In summary, treatment with Rhulief (500 mg twice daily) resulted in similar benefits to patients with OA as celecoxib (100 mg twice daily) for treatment of OA of the knee.

Chandran and Goel, 2012 — Rheumatoid Arthritis

A randomized, single-blinded, three-arm, eight-week, pilot study explored the effectiveness of BCM-95 (500 mg twice daily), diclofenac sodium (50 mg twice daily), and both therapies in combination for treatment of RA.25 The study included 45 patients (38 women and 7 men; mean age, 48 years) diagnosed with active RA (American College of Rheumatology [ACR] functional class I or II and Disease Activity Score 28 [DAS28] > 5). Patients taking NSAIDs or other anti-RA therapy within four weeks of entry into the study were excluded. The primary endpoint was the DAS28 and secondary endpoints were ACR scores. All three treatments caused significant reductions in the DAS28 and ACR scores. Although there were trends towards the greatest improvement in the BCM-95 group in measurements including pain (visual analog scale [VAS]), these differences were not significant. The degree of inflammation was assessed using two different blood measurements: erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). There were no significant differences among groups in the ESR measurements. The BCM-95 group was the only one to demonstrate a reduction in CRP. CRP is a protein produced by the liver during an inflammatory reaction and considered to be a more specific measure of inflammation than ESR. In summary, this study found BCM-95 (500 mg twice daily), diclofenac sodium (50 mg twice daily), and both therapies in combination equally effective in reducing disease scores, with a significantly better safety profile for BCM-95 (14% of the diclofenac group withdrew from the trial due to adverse effects; none withdrew from the BCM-95 group). Curcumin treatment was unique in that it also reduced levels of CRP, demonstrating a potential mechanism for an additional anti-inflammatory effect. This study had the weakness of being open-labeled and thus the evaluations were not blinded.

Cancer Chemopreventive Effects

Das et al., 2010 — Oral Submucous Fibrosis

Oral submucous fibrosis (OSMF) is a chronic precancerous condition characterized by epithelial inflammation and progressive fibrosis of the submucosal tissues.26 As the disease progresses, the jaws become rigid to the point that the sufferer is unable to open his or her mouth. The condition is associated with the chewing of betel quid (areca palm nuts wrapped in betel [Piper betle, Piperaceae] leaves with slaked lime [calcium hydroxide], often in addition to tobacco [Nicotiana tabacum, Solanaceae] or spices). Betel-quid chewing is a habit, similar to tobacco chewing, that is practiced predominantly in Southeast Asia and India.

An open-label, three-arm study explored the potential benefits of BCM-95 or turmeric oil compared to a control for patients who were clinically and histopathologically confirmed as having OSMF. The patients (N = 48) were randomly divided (method not given) into three groups of 16 patients each. They were treated for three months and then followed for an additional six months. Group 1 was given 500-mg capsules of BCM-95 twice daily for a total daily dose of 1 g. Group 2 was administered turmeric oil (supplied by Kancor Ingredients Ltd.); 12 drops of oil were held in the mouth for a period of time before swallowing, twice daily, for a total of 600 mg per day. Group 3 was the control provided as Multinal® tablets (New Ambadi Estates Pvt. Ltd.; Madras, India) containing spirulina (Arthrospira spp., Microcoleaceae), one 500-mg tablet taken twice a day for a total daily dose of 1 g. Upon clinical assessment, the patients were categorized as having mild, moderate, or severe symptoms. Biopsies were conducted ahead of treatment and after three months. Following biopsy, the patients were separated into three grades of disease — early, moderately advanced, and advanced. After three months of treatment, groups 1 (BCM-95) and 2 (turmeric oil) had significant reductions (P values not given) in burning sensations in their mouths and their tolerance for spicy food also had improved in comparison to the control group. Complete relief from mouth pain was reported for those in the BCM-95 and turmeric oil groups within one month of treatment whereas the pain persisted in five patients in the control group. There were significant increases in the ability of patients in groups the BCM-95 and turmeric oil to open their mouths after one month and three months of treatment. These groups both demonstrated an increase of 0.87 cm in mouth opening compared to 0.18 cm in the control group. Those in the turmeric oil group had the greatest improvement in tongue protrusion. Subjects in this group had a change in color of patients’ mucosa, from blanched to erythematous, indicating an increase in vascularity. In addition, three patients in this group had their leukoplakic lesions disappear. The clinical scores were reduced in the BCM-95 and tumeic oil groups after 15 days of treatment. After three and six months, these groups had statistically significant downgrading of clinical scores compared to the control group. After the six-month follow-up period, the turmeric oil group had a better clinical score than those in the BCM-95 group. The histopathology reports from the biopsies taken at baseline and three months indicated that seven patients in the BCM-95 group and nine patients in the turmeric oil group had improved to a better stage, while three patients in the control group deteriorated into the advanced stage. Histopathology reports showed that none of the patients in the BCM-95 or turmeric oil groups had a progression to malignancy. However, the control group showed an increase in mitotic figures, indicating a progression towards cancer. No adverse reactions were reported. All treatment regimens were well tolerated. There were no signs of allergic or adverse reactions. In summary, there was a measured improvement in OSMF following treatment with BCM-95 and with turmeric oil when compared to tablets containing spirulina. A weakness of the study write-up was that the statistical analyses were not included.

Kuriakose et al., 2016 — Oral Leukoplakia

Oral leukoplakia is a white lesion of the mucosa of the oral cavity that is potentially malignant. A multicenter, double-blind, randomized, placebo-controlled trial compared BCM-95 to placebo in subjects with oral leukoplakia that was confirmed both clinically and histologically (via biopsy), more than 15 mm2 in size, and not previously treated. The subjects received either 3.6 g/day of BCM-95 (n = 111) or a placebo of cellulose (n = 112), for six months. At the end of that time, the lesion was measured and another biopsy performed. Those demonstrating a complete response were observed for six months without further intervention. Those with a partial response (50% or greater decrease in size) were continued on their treatment (BCM-95 or placebo) for an additional six months. The primary endpoint was a change in size of the lesion at six months compared to baseline. A reduction in size of at least 50% was observed in 75 subjects in the curcumin and 62 subjects in placebo arm, with a significant difference between groups (P = 0.03). The histological assessments showed no significant differences between groups. Partial responders who received an additional six months of treatment did not display additional benefits. The authors concluded that treatment of oral leukoplakia with curcumin (3.6 g for six months) was well tolerated and produced a significant reduction in the size of lesions compared to baseline and placebo. 

Effects in Patients Undergoing Radiotherapy

Hejazi et al., 2013 & 2016 — Radioprotective Effects

In a randomized, double-blind placebo-controlled study, 40 patients with prostate cancer undergoing treatment with external beam radiotherapy in combination with hormone ablation were randomly assigned to receive BCM-95 (500 mg capsules six times daily, totaling 3 g per day) or placebo (roasted rice [Oryza sativa, Poaceae] flour in capsules).29 The patients all had a life expectancy greater than five years and no detectable metastatic disease. Treatment with BCM-95 or placebo started one week before onset of radiotherapy and continued throughout the radiotherapy. The radiotherapy was given as fractions of 2 Gy, five times a week for roughly eight weeks, with a total dose of 74 Gy. Quality of life specific to prostate cancer was evaluated using a questionnaire (European Organisation for Research and Treatment of Cancer) that assessed urinary, sexual, and bowel function. The questionnaire was completed during face-to-face interviews at baseline (one week prior to radiotherapy) and three months after completion of radiotherapy. At baseline, there were no differences between the groups in urinary symptoms, bowel symptoms, or sexual activity. Comparison of change in urinary symptoms over the 20-week period demonstrated a reduction in urinary symptoms in the BCM-95 group compared to placebo (P < 0.01). Among the urinary symptoms, the greatest improvements were reductions in urination frequency during the day, sleep disturbance due to urination at night, and limitation of daily activity due to urinary problems. There were no comparative differences between groups in bowel symptoms or sexual activity. The authors of the study suggested that BCM-95 might confer protective effects against treatment-related urinary symptoms in patients with prostate cancer that undergo radiation therapy. The authors also suggested the need for additional studies with larger sample sizes and larger doses of curcumin.

In a follow-up publication on this clinical trial, plasma antioxidant levels for participants in the study were reported.34 Blood was drawn one week before the initiation of radiotherapy and three months after completion, and analyzed for total antioxidant capacity (TAC), glutathione peroxide (GPX) activity, superoxide dismutase (SOD) activity, and catalase activity. Intake of antioxidant and pro-oxidant nutrients (vitamin E, vitamin C, zinc, selenium, iron, and copper) and foods containing phenolic compounds was recorded. There were no significant differences in dietary consumption between the two groups. At baseline, the biochemical variables were similar for the two groups, with the exception of TAC which was higher in the curcumin group.In the BCM-95 group, the levels of TAC were significantly higher post-radiotherapy than at baseline (P < 0.001), and the SOD activity decreased significantly from baseline (P = 0.018). No other changes over time were observed for either group. The increase in TAC and decrease in SOD for the BCM-95 group were significant compared to the placebo group after adjusting for baseline differences (P = 0.014 and P = 0.018, respectively). The authors of the study recognized that the use of antioxidants in combination with radiotherapy is controversial. In this study, there was no negative effect due to BCM-95 on the outcome of treatment as measured via prostate-specific antigen (PSA) levels and MRI/MRS images. The authors concluded that BCM-95 improved antioxidant status without compromising the efficacy of radiotherapy.