Reinventing chocolate: the dark-and-sweet side of clinical trials
More and more evidence are piling up on the health benefits of dark chocolate. Cocoa is rich in flavonoids which have potent antioxidant properties. No wonder that the biggest chocolate manufacturers are scrambling to grab this opportunity to reinvent chocolate from being the number one enemy of weight watchers, diabetics and heart patients to be the next “wonder health food” or dietary supplement that might even surpass soy and omega-3`s in terms of popularity. And no wonder that people are scrambling to volunteer to participate in chocolate clinical trials, free of charge. Given below are overviews of some trials on chocolates, past, present, and future.
Successful trials whose results have been published: [1,2]
This “randomized, controlled, investigator-blinded, parallel-group trial” investigated the effect of chocolate consumption (6.3 g of dark chocolate per day = 30 kcal) on the blood pressure of prehypertensive adults. “From baseline to 18 weeks, dark-chocolate intake reduced mean systolic BP by 2.9 mm Hg (p<0.001) and diastolic BP by 1.9 mm Hg (p<0.001) without changes in body weight, lipids, glucose, or 8-isoprostane. Hypertension prevalence decreased from 86% to 68%.”
In this double-blind randomized study, Swiss researchers at the Zurich University Hospital studied the effect of dark chocolate in 22 heart transplant patients. An intake of 40 g of dark chocolate (70% cocoa) “induces coronary vasodilation, improves coronary vascular function, and decreases platelet adhesion 2 hours after consumption. These immediate beneficial effects were paralleled by a significant reduction of serum oxidative stress and were positively correlated with changes in serum epicatechin concentration.”
The not so-successful: [3]
The Chocolate Happiness Undergoing More Pleasantness (CHUMP) study was designed as a double-blinded clinical trial “to compare the effects of dark chocolate, milk chocolate and normal chocolate consumption on happiness.” However, data analysis somehow went awry because “many participants switched groups mid-study because of their personal chocolate preferences. Although the CHUMP study was pleasurable, it demonstrated the difficulties associated with performing a truly blinded clinical trial.”
This one is ongoing:
The Phase I trial on the “Effects of Dark Chocolate on Insulin Sensitivity in People with High Blood Pressure” (ClinicalTrials.gov Identifier: NCT00099476) examines “whether dark chocolate affects the way patients with hypertension (high blood pressure) respond to insulin, a hormone secreted by the pancreas that regulates blood glucose (sugar) levels. In many people with hypertension, insulin is not as effective in helping the body use glucose. This is called insulin resistance. Insulin also increases blood flow into muscle by opening inactive blood vessels. Laboratory studies suggest that eating dark chocolate may improve blood pressure. This study will determine whether dark chocolate improves insulin resistance or changes how blood vessels react to insulin in hypertensive people.”
This one is still recruiting:
This trial, due to start in June, will investigate whether flavonoids found in chocolate and other foods can reduce the risk of cardiovascular diseases in menopausal women with type 2 diabetes. “The study is funded by … Diabetes UK, and is led by a team at the University of East Anglia (UEA) in Norwich, partnered by the Elsie Bertram Diabetes Centre, Norfolk, Norwich University Hospital (NNUH) and the Institute of Food Research (IFR).”
References:
1. Taubert D, Roesen R, Lehmann C, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide. A randomized controlled trial. JAMA 2007; 298:49-60
2. Flammer A, Hermann F, Sudano I, et al. Dark chocolate improves coronary vasomotion and reduces platelet reactivity. Circulation 2007;116:2376-2382.
3. Chan, K. A clinical trial gone awry: the Chocolate Happiness Undergoing More Pleasantness (CHUMP) study. CMAJ 2007; 177 (12).
How Genetic Variation is Affecting Drug Development
In the March 2 issue of the Swiss newspaper “SonntagsZeitung” is an interesting article entitled “Pillen in Massanzug” which can be translated as “Custom-made Pills” [1]. The article basically explores how increased knowledge of human genetics is creating changes in drug development and speculates on the possibility of personalized medicine.
Here are some examples:
Carbamazepine
In December last year, The US FDA recommended genetic testing in connection with the prescription of the drug carbamazepine. Carbamazepine is commonly used for the treatment of epilepsy, bipolar disorder and neuropathic pain. Recently, certain patients – notably of Asian ancestry - were observed to develop serious skin disorders as adverse reaction to the drug. “Studies have found a strong association between certain serious skin reactions and an inherited variant of a gene, HLA-B* 1502, an immune system gene, found almost exclusively in people with Asian ancestry.” [2] Prior to this recent recommendation, genetic testing was recommended for all patients regardless of ethnicity. However, with the recent results of genetic studies, genetically high-risk patients have been narrowed down to an ethnic group, making life easier for health professionals and their patients, as well as the drug manufacturers themselves.
Statins
The use of the anti-cholesterol drugs statins has been associated with muscle pains and weakness. Researchers have recently identified the gene that may hold the key to statin-induced muscle toxicity. The atrogin-1 gene is associated with different types of muscle atrophy. In vitro and in vivo studies show that statins activate atrogin-1 gene leading to skeletal muscle damage [3]. Atrogin-1 gene expression may differ in different people, explaining the wide range of muscle symptoms (from very mild to debilitating) in statin users.
Trastuzumab
The anti-cancer drug Herceptin (trastuzumab) is a HER2/neu receptor antagonist and is indicated only for patients with HER2-overexpressing breast cancer. The drug specifically targets a gene (HER2) that causes breast cancer so that patients with other types of breast cancer cannot benefit from this drug. Considering the rather serious side effects involved (cardiomyopathy and pulmonary toxicity), HER2 gene testing is highly recommended before chemotherapy can be started. [4]
Ezetimibe
Ezetimibe is one of 2 combination drugs tested by the controversial ENHANCE trial. The study participants have heterozygous familial hypercholesterolemia, a genetic disorder characterized by cholesterol deposition and high plasma concentrations of low-density lipoprotein cholesterol [5]. Unfortunately, the trial results did not show any benefit from ezetimibe. However, drug testing on genetically distinct populations is becoming a common practice in drug development.
So how far are we from personalized medications? I personally think this will soon be technologically possible but whether it`s financially feasible is a different matter.
References:
1. SonntagsZeitung, 2 March 2008, p.73
2. FDA News, 12 December 2007.
3. Hanai et al. J Clin Invest. 2007 December 3; 117(12): 3940–3951.
4. Herceptin prescribing information, Jan 2008.
5. Yuan et al. CMAJ • April 11, 2006; 174 (8).
Pediatric clinical trials: damned if you do, damned if you don’t
Drug regulators are in a quandary. On the one hand, they’d rather spare children from being used as test subjects in clinical trials. On the other hand, recent developments show an urgent need for pediatric testing.
There have been recent reports of adverse side effects, some of them fatal, attributed to OTC drugs for children. These concerned seemingly innocuous cough and cold medications containing active ingredients such as pseudoephedrine, paracetamol [1,2], and camphor [3]. But prescription drugs for children`s ailments such as asthma and ADHD are incriminated as well.
This brought to light how very little we actually know about pediatric pharmacology.
The problem lies with the fact that many drugs with well-established efficacy and safety profile have only been tested in adults. With an aging population and low birth rates in developed countries, the pediatric drug market is not really top priority for pharmaceutical industries. Very little money is allocated for pediatric R&D. Pharmacological results were simply extrapolated to pediatric population as “miniature adults.”
The issue is compounded by lack of test subjects. Very few parents in developed countries would ever consent that their children be enrolled in a clinical trial. Most pharmaceutical companies turn to developing countries for testing. Although there are strict guidelines regulating pediatric testing, there are still concerns about adherence to GCP in those countries.
The regulators are now scrambling to come up with solutions to plug this knowledge gap on pediatric drugs.
Last year, the US passed the Best Pharmaceuticals for Children Act 2007 and an amended version (2007) of the 2003 Pediatric Research Equity Act. The Acts empowered the US FDA to require drug companies to test new drugs on children before approval [4]. However, there is still a lack of knowledge on drugs approved before 2003.
In Europe, the EMEA is requiring a pediatric investigation plan for all new drug applications starting July 2008 (unless a non-pediatric use waiver is justified). In addition, it is funding research on off-patent drugs as well as looking into pediatric clinical data that may not have been previously published [5, 6].
In the meantime, millions of children need medications while drugs against cancer, infections, asthma, high blood pressure and hyperactivity currently available are waiting to be tested for pediatric use. Do we use these drugs or not ? Quandary for doctors and parents as well.
Damned if you do. Damned if you don’t.
References:
1. Wingert WE, Mundy LA, Collins GL, Chmara ES. Possible role of pseudoephedrine and other over-the-counter cold medications in the deaths of very young children. J Forensic Sci. 2007 Mar;52(2):487-90.
2. Centers for Disease Control and Prevention (CDC). Infant deaths associated with cough and cold medications–two states, 2005. Morb Mortal Wkly Rep. 2007 Jan 12;56(1):1-4.
3. Press Release, NYC Department of Health. January 17, 2008. Health department warns parents to keep camphor products away from children.
4. US FDA, Pediatric Drug Development. Retrieved 27 Jan 2008.
5. Sinha G.J. EU law mandates drug testing in children. J. Natl Cancer Inst. 2008 Jan 16;100(2):84-5.
6. EMEA Press Release Paediatric Committee (PDCO), 25 Jan 2008.
ENHANCE trial update: no beneficial effects on CA IMT from ezetimibe
The much-awaited results of the “Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression” (ENHANCE) trial are finally out – and they are a huge disappointment.
ENHANCE is an international 2-year, randomized, double-blind, controlled trial which compared the combination of ezetimibe and simvastatin to simvastatin monotherapy.
Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor routinely used in the management of atherosclerosis. The newcomer ezetimibe is a specific cholesterol absorption inhibitor and the 2 drugs supposedly act as complementary agents that can have beneficial effects on the carotid artery intima-media thickness (CA IMT) of atherosclerosis patients. The trial was conducted in 720 patients with heterozygous familial hypercholesterolemia. The primary end point was mean change in the IMT measured at 3 different sites in the carotid arteries [1].
The trial results showed no significant difference in the mean IMT change between patients treated with ezetimibe/simvastatin 10/80 mg vs patients treated with simvastatin 80 mg alone. There was also no significant difference in treatment-related adverse events in both treatment groups. However, ezetimibe was associated with a larger reduction in LDL cholesterol [2].
References:
1. Kastelein et al., 2005. Comparison of ezetimibe plus simvastatin versus simvastatin monotherapy on atherosclerosis progression in familial hypercholesterolemia Design and rationale of the Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial. American Heart Journal 149 (2): 234-239.
2. Hughes, S. 2008. ENHANCE results yield disappointment for ezetimibe. Heartwire 14 Jan 2008.
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Symposium on antiviral applications of RNAi
The European Science Foundation (ESF) and the European Molecular Biology Organization (EMBO) are organizing a symposium on “Antiviral Applications of RNA Interference” on 5 to 10 April 2008.
The symposium will take place in Sant Feliu de Guixols, Spain, located 120 km north of Barcelona.
RNA interference (RNAi) is a promising new technology with a great potential for use as an antiviral tool. The approach allows specific inhibition of gene expression either through the degradation of specific RNA molecules or hindering of transcription of certain genes. The first clinical trials to evaluate the efficacy and safety RNAi technologies have recently been started.
The symposium will mainly focus on human pathogenic viruses and “will be the first comprehensive meeting combining RNAi and antiviral research.”
“The meeting will cover the most recent progress in the field by 22 invited presentations of internationally renowned researchers, complemented by shorter contributed oral presentations of young scientists and by poster presentations.”
The STEP Trial: Discontinuation and Unblinding
The STEP Trial: The STEP study was a phase II multinational, randomized, double-blind, placebo-controlled clinical trial which was started in 2004.
The Investigational Drug: The V520 HIV vaccine candidate is a combination of 3 components made from a weakened adenovirus type 5. The vaccine serves as a vector of 3 synthetically produced HIV genes known as gag, pol and nef. These HIV genes would supposedly induce “an HIV-specific immune response through the body’s own CD8 T-cells, which become programmed to recognize and kill HIV infected cells.”
The Sponsors: The STEP trial was sponsored by Merck, the National Institute of Allergy and Infectious Diseases (NIAID), and the HIV Vaccine Trials Network (HVTN).
The The Study Population: 3,000 HIV-negative participants from different ethnic groups. They are aged between 18 and 45 years of age and at high risk of HIV infection. The trial was conducted in the United States, Peru, Brazil, Dominican Republic, Haiti, Jamaica, Australia, and South Africa.
The Efficacy Endpoints: The primary efficacy endpoints were to evaluate the ability of the vaccine to prevent HIV infection and to reduce virus proliferation in infected individuals.
The Discontinuation: On 21 September 2007, Merck announced the discontinuation of the STEP study due to poor efficacy profile. The vaccine did not prevent infection nor reduce viral loads in the bloodstream of HIV-positive individuals.
The Unblinding: In November 2007, Merck and HVTN announced their decision to unblind the trial based on concerns that the vaccine may actually have induced susceptibility to HIV infection in study participants. Sources:
HVTN Press Release 13 Nov 2007
Nexavar Approved for Liver Cancer Treatment
The US FDA has recently approved the oral kinase inhibitor Nexavar (sorafenib) for use in patients with hepatocellular carcinoma, an inoperable form of liver cancer. This makes Nexavar the “first FDA-approved drug therapy for liver cancer.” Nexavar was originally approved in 2005 for treatment of advanced kidney cancer and is currently marketed in over 60 countries for this indication [1, 2].
The FDA approval came about month after Nexavar was centrally approved in Europe in October for the new indication. The appproval was based on results of a randomized placebo-controlled trial involving 602 patients with hepatocellular carcinoma. The study results showed an average extended survival of 2.8 months in patients treated with Nevaxar compared to placebo. Tumor progression was also observed to be slower.
“Nexavar, an oral anti-cancer drug, is the first approved systemic drug therapy for liver cancer and the only drug therapy shown to significantly improve overall survival in patients with the disease.” [1,2]
Nexavar is manufactured by Bayer Pharmaceuticals Corporation of Germany.
[2] Bayer Press Release, 19 Nov 2007
Avandia Remains on Market but with Additional Warning
The US FDA has recommended that Avandia (rosiglitazone) be allowed to remain on market. However, additional warning has been inserted in the existing boxed warning in the product’s labeling. The new warning highlights the potential increased risk for cardiovascular events, especially myocardial infarction [1].
Avandia, manufactured by GlaxoSmithKline (GSK), was approved for marketing in 1999 in the US as oral treatment for type-2 diabetes mellitus. It has the advantage that it can be used as a stand-alone therapy or as co-therapy with other oral anti-diabetes treatments.
An article in NEJM early this year reported a meta-analysis of 42 randomized controlled clinical trials on rosaglitazone. The results show that “rosiglitazone was associated with a significant increase in the risk of myocardial infarction and with an increase in the risk of death from cardiovascular causes that had borderline significance.” [2]
The FDA has requested GSK to conduct a new long-term postmarketing study to evaluate the potential cardiovascular risk of Avandia and the manufacturer agreed to comply [1]. The study is expected to be concluded by 2014.
Sources:
A Promising Vaccine against Hypertension: Results from a Phase II Trial
An investigational vaccine against angiotensin II being tested by Cytos Biotechnology is showing promise. Results from an exploratory Phase IIa trial were presented at the American Heart Association Scientific Sessions 2007 [1] this month. CYT006-AngQb is a virus-like particle-based conjugate vaccine and is indicated for patients with mild to moderate hypertension. Preliminary results show “a significant reduction of daytime ambulatory blood pressure (BP) and a marked reduction in the early morning hours, when most adverse cardiovascular events occur.” [2]
Currently available antihypertensive drugs have a short half-life and must be taken on a daily basis. CYT006-AngQb has the advantage of producing extended antibody response with a half-life of about 4 months [2, 3].
In addition to a good efficacy profile, CYT006-AngQb was reported to be well-tolerated. The most common adverse events reported were pain, erythema, or edema at the injection site, and headache. All events were transient and no drug-related adverse events were reported during the 12-month follow-up period [3].
If approved, the vaccine would be a major breakthrough in the long-term management of hypertension.
Sources:
2 Medscape
Safety issues with prasugrel: the latest from TRITON-TIMI 38
TRITON-TIMI 38 is one of the biggest phase III clinical trials on prasugrel, a new thienopyridine from Lilly/Daiichi Sankyo. The trial was designed as multicenter, randomized, double-blind, and parallel-group. Over 13000 patients from different countries were enrolled based on the main inclusion criterion of having moderate- to high-risk ACS and undergoing PCI. Of these, about 73% had unstable angina/non-ST-segment elevation MI and 37% ST-segment elevation MI [1, 2].
The participants were randomized to either prasugrel or the comparator clopidogrel. Clopidogrel combined with aspirin is the first line antiplatelet therapy for the prevention of thrombotic complications of PCI. Prasugrel is said to be less variable and achieves a higher level of platelet inhibition than the comparator. The primary end point of the trial is the time of the first event of cardiovascular death, MI, or stroke [1, 2].
The latest results from the trial as reported in the latest issue of NEJM [3] show good efficacy profile but fall short in terms of safety. Prasugrel significantly reduced cardiovascular events compared to clopidogrel. However, the incidence of bleeding in prasugrel patients was significantly higher. The risk of bleeding is especially elevated in patients who have had CABG or cerebrovascular problems [3]. Safety concerns in terms of bleeding were actually reported already last year at the World Congress of Cardiology in Barcelona, Spain [4].
Abbreviations:
TRITON_TIMI 38: TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel Thrombolysis In Myocardial Infarction 38.
ACS: acute coronray syndrome
PCI: percutaneous coronary intervention
MI: myocardial infarction
CABG: coronary artery bypass graft
Sources:
- TIMI homepage
- American Heart Journal 152(4):627-635, October 2006
- NEJM 357:2001-2015 November 2007.
- Heartwire 21 September 2006