Sonntag, 13. November 2016

Large ongoing Primary Prevention Studies

In this article I want to highlight large studies that are being performed in relatively healthy populations, or which provide relevant data to further the goal of delaying aging and age-related diseases.

To provide a complete picture I looked into various reviews and the notes and ideas I already had. Keeping track of new nutraceutical and health related developments used to be a big pastime of mine so I hope the below list is somewhat complete. In addition to literature search, I queried a large clinical trials database using various terms. One variation was for example a query for "Interventional Studies | mortality | Adult | Phase 3, 4 | Studies with safety issue outcome measures" yielding 1107 hits. From this list, I selected studies with n > 1000 which yielded approx. 255 results, which were then hand search. In this way the clinicaltrials database helped me to identify a few studies I would have missed otherwise and what follows are short notes on interesting trials.
from (1):
... given the above evidence [from SU.VI.MAX and the Linxian Chinese Cancer Prevention Trial] that low-dose vitamin and mineral supplementation could prevent cancer [almost exclusively in men or nutrient deficient populations], a novel clinical trial (COSMOS; NCT02422745) was initiated in 2016 to test a multivitamin supplement comprising all essential low-dose vitamins and minerals among 12,000 women and 6,000 men with 4 years of treatment and follow-up. The results of COSMOS are not expected for several years.

Omega 3
To date, VITAL is the only ongoing large randomized trial testing n-3 fatty acids for the primary prevention of cancer in a general population (25,874 men and women in the USA)

from (2): Most studies are in special populations e.g. diabetes or elderly or in those at moderate to high CVD risk. Trials have a combined n of almost 60 000 and most studies are expected to finish around 2020. Nevertheless the data will be useful to clarify the role of aspirin in chemoprevention, because people at moderate/high risk of CVD usually have a close to normal risk of cancer.

ACCEPT-D - diabetes
ARRIVE - 10-20% 10yr CVD risk
ASPREE - elderly
ASCEND - diabetes
TIPS-3 - healthy at risk of CVD, only study with primary endpoint cancer

COMPASS, a study of rivaroxaban, ~24 000, >65yo patients with coronary artery disease, finishes around 2018, The interesrting part is the pantoprazole and aspirin arm. The aspirin arm should be large enough to provde cancer data and we may find out if pantoprazole negates any benefits of aspirin and how much it helps to mitigate side-effects.
CARING study, diabetes, n~3000 evaluates morning vs evening dosing of Aspirin

ADD-ASPIRIN (7) n~10 000, secondary prevention of cancer through aspirin

Vitamin D
Trials with a combined sample size of over 100 000 are ongoing (VITAL, VIDAL FIND and "D-Health, Australia" plus a large number of mid-sized studies). I am a little skeptical that this is efficient resource use even though I am cautiously optimistic about vitamin D in general.

TAME study led by Nir Barzilai (5).
"In the TAME study, we plan to enroll 3,000 subjects, ages 65–79, in 14 centers across the U.S. Rather than study the effects of metformin on each separate condition, we will measure time to a new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality. TAME will also assess important functional and geriatric end points."

PCSK9 inhibitors
Primary prevention in high risk patients (example), but we are still waiting on data in other groups.

Alzheimer's disease and cognition

PREADVICE (SELECT substudy, n~4000)
 Vitamin E +/- Selenium (200ug/d)

"Multidomain" studies ("physical exercise with cognitive training, nutritional intervention")
Not enough effort is put into such studies but a few projects of moderate size are ongoing (4):
"Of note, three of the ongoing multidomain trials (two of which are partly published75 and 82 and one of which is registered [ identifier NCT01745263]) involve between 1680 and 3700 participants and have up to 6 years of follow-up, including one75 that has dementia incidence as the primary outcome."

More discussion can be found in this paper. A lot of successful multidomain/multi-intervention studies are getting extended follow-up it seems (FINGER, MAPT, PreDIVA).

The authors also discuss drug studies in asymptomatic individuals:
The ADCS-A4 study ( NCT02008357) [88] is a placebo-controlled, potential label-enabling RCT conducted in 1150 asymptomatic individuals (aged 65–85 years) who show brain Aβ accumulation (on positron emission tomography [PET] imaging scans) and are thus considered at risk of AD [80]. The goal is to assess whether administration of anti-amyloid therapy prior to symptoms onset prevents dementia....

Other RCTs among asymptomatic individuals include: the PREVENT Alzheimer Program launched by the Centre for Studies on Prevention of AD (StoP-AD) at the Douglas Mental Health University Institute (Montreal, Canada), which will test preventive interventions (naproxen, nasal insulin or others) in older adults with a family history of AD [89]; and the TOMORROW trial ( NCT01931566), a multicenter label-enabling trial that tests whether a potential disease-modifying drug (Pioglitazone [Takeda]) can postpone the onset of MCI due to AD, and whether a genetic-based (using APOE4 and TOMM40) biomarker risk algorithm predicts risk of MCI due to AD.

Blood pressure lowering and dementia
SPRINT MIND, n~9000 SBP<120 mmHg (4)
"more than 9000 individuals aged 50 years and older with raised systolic blood pressure who are free of stroke and diabetes, treated for up to 6 years... This study will therefore be one of the largest dementia prevention trials so far and will include both middle-aged and elderly adults, which is important because the benefits of blood pressure lowering might be age dependent."

Physical activity & CVD
A substudy of WHI, the Women's Health Initiative Strong &Healthy (WHISH) trial will enroll n~ 50 000 older women and test physical activity for CVD prevention.

Combined chelation + multivitamin
TACT2 - will test chelation + a high dose multivitamin in patients at relatively high risk for CVD. From what I read, TACT1 was a badly designed study testing a flawed treatment idea. This one doesn't look much better.

Polypill research is extremely important to interventional biogerontologists
the miracle treatment against non-adherence and the future for most anti-aging pills

Levels of adherence in secondary prevention, irrespective of the assessment tool, have consistently been shown to be about and indirect costs of non-adherence to chronic treatments have been calculated between $100billion and $289billion annually in the US...
Three of the four common polypill drugs lead to modest liespan extension in the mouse, statins & ACE inhibitors (9) and aspirin (10):
The concept of the CV polypill is now more than a decade old. It was originally proposed in 2001 by a WHO and Wellcome Trust expert group [13] and subsequently specified as a combination of four drugs (beta-blocker, angiotensin converting enzyme [ACE] inhibitor, aspirin and a statin), which was estimated to reduce CVD events by 75% in people with clinical evidence of CVD.

There is a huge fear of treating "healthy" people ammong doctors and health professionals:
Reservations about this CV prevention strategy certainly are multifactorial, but a decisive part has clearly been played by the original interpretations of the role of the polypill and its possible indications. In 2003, Wald and Law claimed that a polypill containing six components and administered to each individual older than 55 years, irrespectively of their risk factors status, would reduce the incidence of cardiovascular disease by more than 80% [15]. This “vaccination approach” found strong opposition among the scientific community because of the unknown consequences of medicalizing an entire population, the costs of potential adverse reactions, psychological effects in a healthy population, as well as the possibility of promoting unhealthy lifestyle habits. Without suitable clinical studies demonstrating its efficacy, this strategy is unlikely to gain the acceptance of health care professionals and regulating authorities.
So far ongoing studies are limited to secondary prevention and primary prevention in at risk subjects:
1. Indian (international) Polycap Trial (TIPS)-3, n~5000, no Aspirin according to this reference (8) but refernce (2) claims otherwise.
2. Heart Outcomes Prevention Evaluation (HOPE)-3, n~12500, statin + blood pressure lowering. Completed in the mean time.
"evaluating the concept of combined BP and cholesterol lowering medications in individuals without vascular disease and with average BP and cholesterol levels"
3. HOPE-4, 4. Iranian polypill study.

Iranian polypill study
n<2400(?), cf PMID: 26265520, completion date 2018
"Polypill taken once daily for 5 years. Each pill contains acetylsalicylic acid 81 mg, atorvastatin 20 mg, hydrochlorothiazide 12.5 mg, valsartan 40 adults older than 50."
From what I can see the polypill (n~3500) wil be compared to minimal care (n~3500) as well as standard care (n=24 000, c.f. ref. 8). I don't think minimal care would fly under FDA  or EMA rule and this is something to keep in mind. Solid trials of anti-aging drugs might be considered too risky by "our" standards and this may lead to reasonable studies in "developing" nations one day. It's easier to envision a high risk/reward Rapamycin study in China than the US at this stage, for instance.

Screening for cancer (a brief look)
Although, screening is not the focus of this post, I'd like to mention a few ongoing studies. There's improved mammography for women with "dense" breasts using MRI (6) n~28 000.
A Spanish study will "compare the efficacy of biennial immunochemical fecal occult blood test (iFOBT) versus colonoscopy every 10 years for the reduction of colorectal cancer-related mortality at 10 years in average-risk population.", n~55 000.
The "NORCCAP: Norwegian Colorectal Cancer Prevention Trial" is testing the addition of fecal blood test to sigmoisdoscopy. n~100 000. Some results have been published before.
And a similar Norwegian study pits the fecal blood test vs sigmoidoscopy.

H. Pylori screening and treatment
This reminds me of a provocative post I wrote suggesting that perhaps everyone should get tested for H. Pylori. Newer studies could help us get a better grasp of the risks and benefits of mass screening and put my hypothesis to the test.

HELPER study in S. Korea, n~11 000, completion date 2026
"There is sufficient epidemiological and experimental evidence supporting a causal link between bacterial infection with H. pylori and gastric cancer development. However, evidence from clinical trials on the efficacy of H. pylori eradication with antimicrobial therapy to reduce the risk of gastric cancer is still limited. In addition, the beneficial or deleterious health impact of mass eradication at the population level has not been defined."
Although, let's not forget that Korea has one of the highest rates of stomach cancer in the world, certainly shifting the risk-reward ratio.

HEAT (Helicobacter Eradication Aspirin Trial), 33 000 a large simple double-blind placebo controlled outcomes study of Helicobacter pylori (H. pylori) eradication to prevent ulcer bleeding in aspirin users. It will be run by the University of Nottingham, with recruiting centres across the UK. This trial is funded by the National Institute of Health Research Health Technology Assessment (NIHR HTA) Programme.
Aspirin use is widespread and increasing in elderly patients. The main hazard is gastrointestinal bleeding, which may be increasing because of increasing aspirin use. This trial is based on evidence that peptic ulcer bleeding in aspirin users occurs predominantly in H. pylori positive people.

Summary and suggestions for future studies
To start with, I realize it is a little arrogant to claim better knowledge of potential drug candidates and interventions than the whole research and funding world. That's not what I am doing, however. Instead I want to point out ideas that many other researchers, gerontologists, clinicians and nutritionists would agree with. It is clear that funding is often limited and biased towards flashy, hyped up ideas (vitamin D) or set in stone dogma that dies only slowly (multivitamins). Reading the literature I realized that my first intuition was completely right, too many projects chasing too little money and hence many decent ideas lose out.

If there is any glaring omission this is it. The health benefits of blood donation (or any blood loss) have been discussed for decades. So what I am missing the most, is a large phlebotomy study to decrease ferritin and tissue iron burden in men and post-menopausal women. The preliminary evidence from the FeAST trial is better, much better than anything I can muster for vitamin D.

On the other hand, I am quite pleased to see so much research on Aspirin but I would have prefered more studies focused on primary prevention of cancer and on side-effect mitigation. So I'm happy to see the HEAT study on H. Pylori and Aspirin side-effects as a positive exception here.

The polypill studies aren't optimal and I think we could do better by designing relevant studies based on the NIA's ITP program in addition to clinical evidence. These studies would combine drugs that are safe in humans and extend mouse healthspan and lifespan, i.e. statins, blood pressure lowering drugs, metformin and aspirin as well as a proton pump inhibitor or a prostaglandin. We could use a polypill or factorial design. Importantly, we need to target the general population to pave the way for better "true" anti-aging therapies and to alter the regulatory landscape.

The nutrition and supplement studies are quite terrible and I can say this with confidence even though I haven't kept up with the literature over the last year or two. It's mostly a funding issue, I am sure. Omega 3/fish oil studies are a sad reminder that we aren't performing enough research on other oils and fat sources. The key studies to do, would use olive oil, nuts and flax seed oil in primary prevention. The over-funding of vitamin D studies is a symptom of too conservative, hype-based funding, something more daring could be done with part of that money. Vitamin K, magnesium and potassium have some promising data behind them. B vitamins are dead for primary prevention. Iodine and lithium deserve small scale studies. There's not enough preliminary data on copper/zinc as far as I can tell. Also, I'm not commenting on vitamin E, carotenoids and related substances because I know too little on this subject.  Multivitamin studies are being performed in at-risk populations, which is fine.

Phytonutrients and carninutrients (creatine, beta-alanine, taurine etc.) merrit small scale studies except perhaps creatine (at least it's safe). I would be literally scared of the outcome of studies run with some phytonutrients (e.g. plant sterols, dietary fibre), but how are we ever to resolve the controversy if not by hard outcomes? While with other phytonutrients I still see no way forward to isolate and standardize the key substances, e.g. with flavonoid-related substances (chocolate, tea, wine, fruits, berries - yes, it's that heterogenous!), catechins (tea) or isothiocyanates/glucosinolates (cruciferous veggies). Mixtures and extracts from foods stand some chance, but there might be technical difficulities in producing a pill or shake or powder for a study. Matrix effects could be another problem since it will be impossible to replicate the normal dietary intake and interactions in a mixture of foods.

Nutrition studies using whole foods (and beverages) are tricky because they are extremely expensive if you provide the food and otherwise adherence is weak and, in addition, blinding is difficult and the control group must be chosen carefully. Just to throw out an idea, a low meat/vegetarian intervention could be co-funded or crowdfunded by vegetarian friendly activist groups. Studies could provide key foods or enforce a dietary pattern (e.g. Mediterranean diet, plant-focused etc.). 3-5 foods provided in a (factorial?) study design could make for an interesting trial. We could use e.g. whole-grains (somewhat controversial), coffee, herbs/spices (controversial), green tea, red wine, berries, tree nuts, legumes, chocolate, specific fruits and vegetables,

Before this post gets too long perhaps allow me a brief detour to more bona fide supplements***. Little promising research on the horizon. Glucosamine might be a rising star and a combined mortality, morbidity, joint health study could (should?) take off some time soon. There's really not much else I can think of, but I haven't kept up with potential new literature so maybe I missed something.
To end on a positive note, carnosine (beta-alanine) and lysine merrit small- or mid-scale studies and, to give another example, cinnamon looks interesting and should be studied in small studies with surrogate endpoints.

***What's a real supplement anyway? There's not much distinction here, but I do my best to distinguish "trying to replicate extremely healthy dietary patterns using physiologic amounts of nutrients" from slightly less physiologic approaches (e.g. lysine bolus or glucosamine, which is uncommon in healthy dietary patterns)

1. Nat Rev Endocrinol. 2016 Jul;12(7):407-20. doi: 10.1038/nrendo.2016.54. Epub 2016 May 6.
Dietary supplements and disease prevention - a global overview.
Rautiainen et al.

2. Aspirin for Disease Prevention: Public Policy or Personal Choice?Aspirin for Disease Prevention

3. J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):252-6. doi: 10.1016/j.jsbmb.2015.04.006. Epub 2015 Apr 9.Update on the Vitamin D and OmegA-3 trial (VITAL).Pradhan AD1, Manson JE2

4. Andrieu, S., Coley, N., Lovestone, S., Aisen, P. S., & Vellas, B. (2015). Prevention of sporadic Alzheimer's disease: lessons learned from clinical trials and future directions. The Lancet Neurology, 14(9), 926-944.

5. Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a tool to target aging. Cell Metabolism, 23(6), 1060-1065.

6. Radiology. 2015 Nov;277(2):527-37. doi: 10.1148/radiol.2015141827. Epub 2015 Jun 23.
MR Imaging as an Additional Screening Modality for the Detection of Breast Cancer in Women Aged 50-75 Years with Extremely Dense Breasts: The DENSE Trial Study Design.

7. Contemp Clin Trials. 2016 Oct 21;51:56-64. doi: 10.1016/j.cct.2016.10.004. [Epub ahead of print]
ADD-ASPIRIN: A phase III, double-blind, placebo controlled, randomised trial assessing the effects of aspirin on disease recurrence and survival after primary therapy in common non-metastatic solid tumours.

8. Castellano, J. M., Bueno, H., & Fuster, V. (2015). The cardiovascular polypill: clinical data and ongoing studies. International journal of cardiology, 201, S8-S14.

9. Spindler, S. R., Mote, P. L., & Flegal, J. M. (2016). Combined statin and angiotensin-converting enzyme (ACE) inhibitor treatment increases the lifespan of long-lived F1 male mice. AGE, 1-13.

10. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice.
Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE.
Aging Cell. 2008 Oct;7(5):641-50. doi: 10.1111/j.1474-9726.2008.00414.x.

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