June 30 NEJM: Adverse Events Associated with Testosterone Administration

[Michael Scally MD]

This is hot off the NEJM press. It will be out tomorrow. I want to caution any extrapolation of the findings to TRT in general. One only has to look at the study population - elderly community dwelling men. If needed, I will comment after reading the article in detail.

There are a few hints what this study might be about for the future. As we know, SARMs are being developed by GTx (GTXI) and Ligand (LGND). It is critically important to establish meaningful endpoints for FDA approval. Bhasin is a large player in the androgen field, if not the biggest. His association with LGND should not go unnoticed!

Dr. Bhasin reports receiving consulting fees and payments for travel or accommodation expenses from Novartis and GlaxoSmithKline and grant support from Solvay Pharmaceuticals, Merck, and Ligand Pharmaceuticals. Testosterone and placebo gel for the study were provided by Auxilium Pharmaceuticals, Norristown, PA.


Basaria S, Coviello AD, Travison TG, et al. Adverse Events Associated with Testosterone Administration. N Engl J Med:NEJMoa1000485. NEJM -- Adverse Events Associated with Testosterone Administration

Background: Testosterone supplementation has been shown to increase muscle mass and strength in healthy older men. The safety and efficacy of testosterone treatment in older men who have limitations in mobility have not been studied.

Methods: Community-dwelling men, 65 years of age or older, with limitations in mobility and a total serum testosterone level of 100 to 350 ng per deciliter (3.5 to 12.1 nmol per liter) or a free serum testosterone level of less than 50 pg per milliliter (173 pmol per liter) were randomly assigned to receive placebo gel or testosterone gel, to be applied daily for 6 months. Adverse events were categorized with the use of the Medical Dictionary for Regulatory Activities classification. The data and safety monitoring board recommended that the trial be discontinued early because there was a significantly higher rate of adverse cardiovascular events in the testosterone group than in the placebo group.

Results: A total of 209 men (mean age, 74 years) were enrolled at the time the trial was terminated. At baseline, there was a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity among the participants. During the course of the study, the testosterone group had higher rates of cardiac, respiratory, and dermatologic events than did the placebo group. A total of 23 subjects in the testosterone group, as compared with 5 in the placebo group, had cardiovascular-related adverse events. The relative risk of a cardiovascular-related adverse event remained constant throughout the 6-month treatment period. As compared with the placebo group, the testosterone group had significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load.

Conclusions: In this population of older men with limitations in mobility and a high prevalence of chronic disease, the application of a testosterone gel was associated with an increased risk of cardiovascular adverse events. The small size of the trial and the unique population prevent broader inferences from being made about the safety of testosterone therapy. (ClinicalTrials.gov number, NCT00240981 .)

[Michael Scally MD]

The negative news is busting out all over. This will spread doubts among TRT practitioners as did the earlier NEJM article. From the appearances, the pendulum is swinging back towards NO TRT except under the most strict guidelines. As I said before, being in NEJM alone will cause almost all to read and listen. IT IS VERY SIGNIFICANT THE STUDY WAS STOPPED EARLY. [Note: this is not good for Auxilium stock and probably AndroGel.]


NIH - Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men
Treatment Phase of Clinical Trial Halted
Adverse Cardiovascular Events Reported in Testosterone Trial in Older Men, June 30, 2010 News Release - National Institutes of Health (NIH)

A clinical trial of testosterone treatment in older men, reported June 30 online in the New England Journal of Medicine, has found a higher rate of adverse cardiovascular events, such as heart attacks and elevated blood pressure, in a group of older men receiving testosterone gel compared to those receiving placebo. Due to these events, the treatment phase of the trial was stopped. The study was supported by a grant to Shalender Bhasin, M.D., at Boston Medical Center from the National Institute on Aging (NIA), part of the National Institutes of Health.

Decreased muscle strength may contribute to difficulties in mobility, such as in walking or climbing stairs, which can limit older persons’ independence. Testosterone treatment has been shown to improve muscle strength in some older men, but it is not yet known whether it would reduce mobility limitations in older men with low testosterone levels. The TOM (Testosterone in Older Men) Trial was designed to address this question. It was a randomized, double-blind, placebo-controlled clinical trial of the effects of six months of testosterone gel treatment on strength and ability to walk and climb stairs in 209 older men with low testosterone levels and mobility limitations. The testosterone gel used in this study was administered to the skin daily. The 209 men in the trial had an average age of 74 and high rates of chronic diseases such as diabetes and cardiovascular disease.

The treatment phase of the trial was stopped on Dec. 31, 2009, following a review by the study’s Data and Safety Monitoring Board (DSMB). The DSMB is an independent panel of medical and statistical experts set up from the start of the trial to check regularly for the occurrence of adverse health events in participants and to detect any possible risks from treatment. In December 2009, the board found that 23 of the 106 men who had received testosterone experienced adverse cardiovascular-related events during the study, compared to five of the 103 men who received placebo. The cardiovascular-related events included heart attack, heart rhythm disturbances and elevated blood pressure, and one death from a suspected heart attack. The DSMB weighed the severity of the adverse events in relation to the potential benefits and recommended that participants stop taking study medications and that enrollment be stopped.

As soon as the DSMB made its recommendation, the treatment phase of the trial was halted. All participants were promptly notified and asked to meet with study physicians to discuss any questions they might have. The men who experienced cardiovascular events were treated by their personal physicians for their specific conditions. No new participants will be enrolled in the study. The study team will continue to monitor the health of all participants for at least another year after stopping testosterone use to further evaluate effects of the treatment.

The report in the New England Journal of Medicine provides detailed information about the outcomes and adverse events in participants. The authors note that physicians and patients, especially older men, should consider this study’s findings on adverse effects along with other information on the risks and benefits of testosterone therapy. They also note that further research is needed to clarify the safety issues raised by this trial.

The authors caution that the ability to draw broader conclusions about the safety of testosterone therapy based on these findings is constrained by several factors, including this study’s small size and the fact that the study’s population was older and had higher rates of chronic diseases and mobility limitation than individuals in most other studies.

In addition, the trial’s eligibility criteria excluded men with severely low testosterone levels, limiting the ability to make inferences about safety in this population. The authors also note that the testosterone doses and serum levels in this trial may be higher than those usually used in clinical practice and in some previous clinical trials.

NIA is funding six other trials studying the effects of testosterone. All of the principal investigators of those trials and their DSMBs and Safety Officers have been informed of the findings in the TOM Trial. After reviewing these findings, and other evidence relating to safety of testosterone treatment, the DSMBs and Safety Officers recommended continuation of the trials, with provision of additional information to participants and additional safety precautions. NIA has reviewed these recommendations and concurs with them.

[Michael Scally MD]

This is from Reuters!!! Take a look at the headline. This is TROUBLE for TRT. I state the limited interpretation of the study, but do you really think most physicians read these studies in detail?


UPDATE 1-Testosterone gel linked to heart problems
UPDATE 1-Testosterone gel linked to heart problems | Reuters

5:59pm EDT

* Older men with poor mobility studied

* Side effects spur early end to test

* Treatment improves strength, muscle mass

(Adds comment from company paragraphs 11-12,16)

By Gene Emery

BOSTON, June 30 (Reuters) - Testosterone treatments may build muscle mass in older men, but they may carry a risk of heart problems in people with poor mobility, U.S. researchers said on Wednesday.

The Massachusetts study, reported online by the New England Journal of Medicine, was halted after six months because the men using a hormone gel were developing so many heart, breathing and skin problems compared to patients applying a placebo gel to their shoulders or upper arms every day.

"I think the study raises important questions about the safety of giving testosterone to older individuals," Dr. Shalender Bhasin of the Boston University School of Medicine said in a telephone interview.

Levels of testosterone, the so-called male hormone, decline with age in men. Supplementing it in healthy men can build muscle mass and strength and lower the risk of disability.

The new test was the first to assess its effectiveness in men over 65 who already had mobility problems such as difficulty walking two blocks or climbing 10 stairs.

The 209 volunteers, with an average age of 74, also tended to suffer from obesity, diabetes, high blood pressure and high cholesterol at the start of the test. "One would expect that from a frail, older population," said Bhasin.

Recipients of the testosterone gel, sold under the brand name Testim by Auxilium Pharmaceuticals (AUXL.O: Quote, Profile, Research, Stock Buzz), became better at walking up stairs and performing chest- and leg-press exercises.

But by the time the study was terminated, 23 patients in the testosterone group and five in the placebo group had experienced a bad side effect such as fainting, chest pain or heart attack. One man in the testosterone group died of a suspected heart attack.

The numbers were too small to be statistically significant and the side effects encompassed a lot of different diagnoses, which may mean that chance played a role in the results.

Yet men receiving testosterone had more serious side effects and more side effects considered to be life-threatening, the researchers said, lasting for three months after the trial ended.

"The study was designed to study mobility limitation, a common syndrome with the elderly that predicts disability, poor quality of life and mortality," Auxilium said in a statement.

"We believe these men are not representative of the typical testosterone replacement therapy population."

Bhasin was surprised by the finding.

"Testosterone is not currently approved for older men with age-related decline or mobility problems," he said. However it is approved by the U.S. Food and Drug Administration for other patients.

Doctors thinking of prescribing testosterone for their older patients should realize that the treatment may pose a serious risk, Bhasin said. "There may be safety issues that they should weigh in their decision," he said.

Testosterone causes salt and water retention and that could have been a factor, the researchers said. The National Institute on Aging, which paid for the trial, also noted that the men in the study may have been getting exceptionally high doses of testosterone. Auxilium said they were getting double to triple the recommended dose.

[Michael Scally MD]

When I said this means BAD NEWS for TRT, I was being serious. In less than an hour since its release, the news is spreading on some widely read news services. Their headlines say it all. [Auxilium Pharmaceuticals, Inc. is down ~5% in AH trading. This will hit other companies. I do not know how much testosterone makes up their revenue, but if it is significant, I expect the share price to be hit.]


Bloomberg News
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study - Bloomberg

Bloomberg BusinessWeek
Auxilium Testosterone Gel Linked to Heart Problems in Older Men
Auxilium Testosterone Gel Linked to Heart Problems in Older Men - BusinessWeek

Wall Street Journal
Testosterone Trial Was Halted Over Cardiovascular Events
Testosterone Trial Was Halted Over Cardiovascular Events - Health Blog - WSJ

[CubbieBlue]

Originally Posted by Michael Scally MD

When I said this means BAD NEWS for TRT, I was being serious. In less than an hour since its release, the news is spreading on some widely read news services. Their headlines say it all. [Auxilium Pharmaceuticals, Inc. is down ~5% in AH trading. This will hit other companies. I do not know how much testosterone makes up their revenue, but if it is significant, I expect the share price to be hit.]


Bloomberg News
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study
Auxilium Testosterone Gel Linked to Heart Problems in Older Men in Study - Bloomberg

Bloomberg BusinessWeek
Auxilium Testosterone Gel Linked to Heart Problems in Older Men
Auxilium Testosterone Gel Linked to Heart Problems in Older Men - BusinessWeek

Wall Street Journal
Testosterone Trial Was Halted Over Cardiovascular Events
Testosterone Trial Was Halted Over Cardiovascular Events - Health Blog - WSJ

Kind of neat watching this all unfold.

Mike can you explain SARMs a little bit? How do they work?

If you can include some sort of handy analogy I would appreciate it

[TheOldFart]

So they were trying to keep men with an average age of 74 and with high % of hypertension and diabetes and other problems at between 500 and 1000 ng/dl, giving them up to 3 tubes of Testim daily. I don't know, but in my opinion, that is sort of nuts. I wonder what the outcome might have been if they had shot for levels between 400 and 600.

The differences in strength are just amazing to me, especially since the average T level at baseline was about 240. Not good, but not as bad as some men are in their 40s.

I don't think this will have the impact that the WHI study on estrogen and progesterone had for women, but then I might be wrong because of the bad reputation that androgens have. The WHI study was on over 10,000 women of all ages and health condition and this is a small study of unhealthy men. I would hope that most doctors will see that this study has little implications for the majority of the population. Even now, most doctors think that giving estrogen to women is fine. My wife's GYN and her 2 GYN ONCs have no problem with it, except that one of the GYN ONCs won't use it for women who have had ovarian cancer. The other one uses it routinely for his cancer patients. Hopefully most doctors will think the same with testosterone for men. I think that my doctor will.

Just as in the WHI study, the news will tout the negative results in a dramatic headline that leaves out all the real data and implications. My wife immediately stopped her estradiol patch when it came out, even though her doctor didn't want her to. Then when I read the real results of the WHI study, we realized that it was a mistake for her to stop. She is much better since restarting it and both of her doctors agree.

[BrianSS]

This is completely irresponsible.

So they gave sedimentary elderly men, in assisted living, with chronic health problems (including heart conditions), 2 to 3 times the recommended dose of testosterone? This sounds like murder to me.

[TheOldFart]

Dr. Scally, what was that June 16 NEJM study that determined that only 2% of men between 40 and 80 have hypogonadism? What was their definition of hypogonadism - 250, 300, etc? I find that 2% number hard to believe.

[Michael Scally MD]

Originally Posted by TheOldFart

Dr. Scally, what was that June 16 NEJM study that determined that only 2% of men between 40 and 80 have hypogonadism? What was their definition of hypogonadism - 250, 300, etc? I find that 2% number hard to believe.

It was 320 ng/dL (adjusted for a laboratory reference range). And you are so right in pointing out that article appeared in NEJM (less than a month ago). This will impact TRT.

[techlogik]

This is one of the most flawed studies I could imagine.

So let's sum this up.

They take a bunch of 74yr old, fat, sedentary men with pre-existing conditions, they slap upwards of 15G/Day of Gel onto them, they don't monitor and test the E2 levels during this study...and they wonder why they had a bunch of complaints and issues?!!?

Are you kidding me? They either have a blatant and obvious bias to show that somehow a topical gel/Test HRT treatment is dangerous for other motives, or they are clearly incompetent fools who shouldn't be in the medical and research field.

If I take 10G of day of gel, and I am a terrible transdermal absorber, I am in the 800+ range on a 1000 scale. I can't imagine what 10-15G a day would do to an old, sedentary unhealthy man with other medical conditions...wait, actually I can, I would predict the same outcome they did without wasting nearly as much time and money, unless it was for a specific reason to make it look this way to begin with.

Unreal...