Verapamil Starts a Phase-II Trial
Verapamil is a drug which has been used in the US since 1982 for high blood pressure, migraines, and heart problems. It also lowers levels of a protein called TXNIP. The researchers running this trial believe this is important because they believe TXNIP kills beta cells as part of the onset of type-1 diabetes. So giving Verapamil should lower TXNIP which should improve beta cell survival, and stop type-1 diabetes. In addition TXNIP is known to lower inflammation, and that might have an effect on type-1 diabetes as well. TXNIP worked in mice trials (but see discussion below).
Drs. Anath Shalev and Fernando Ovalle at the University of Alabama at Birmingham have started a clinical trial. They are enrolling 52 adult, honeymoon type-1 diabetics; half will be treated, half are a (double blind) placebo control group. Patients will get Verapamil for a year, at the same doses that it is commonly prescribed. The primary end point is C-peptide levels after a meal. The researchers will also track several other outcomes: insulin usage, A1Cs, TXNIP, beta cell markers, glucose generation, and two measures of BG stability. They expect to finish in July 2017, which breaks down to about 1 1/2 years to recruit all the patients, and 1 year to run the trial.
This study is funded by JDRF, and is being conducted at The University of Alabama at Birmingham. Contact information is:
Tiffany H Grimes, RN 205-934-4112 email@example.com
Kentress Davison 205-934-4112 firstname.lastname@example.org
Clinical Trial Record: https://clinicaltrials.gov/ct2/show/NCT02372253
Mouse study: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3314354/
Discussion and Opinions
There is a lot to like about this trial. Using an already approved drug means they don't need to do a phase-I trial; they can start out with a larger group. It also means if they report good results, off label use becomes a possibility, and could result in much faster availability.
I particularly like the list of outcomes these researchers will measure. C-peptide (their primary outcome) is the surrogate end point recommended by the FDA for type-1 cures. But they are also watching insulin usage, A1C numbers, and BG stability, which are of practical importance to people with type-1. Finally, they are tracking several biochemical changes which should help them understand what is happening "on the inside".
On the downside, they are only recruiting adults. That's unfortunate, because it will take them much longer to find 52 honeymooning adults, than 52 honeymooning children. (I know that sentence only makes sense in the world of type-1 diabetes.) Since the drug is already approved, it's too bad they could not include the people who are most likely to be in the honeymoon phase. But Verapamil is typically prescribed for high blood pressure or angina, so I suspect there is not much experience giving it to children.
My Opinions About Those Mice....
These researchers have succeeded in preventing type-1 diabetes in mice, by treating during the mouse honeymoon. But I don't put much stock in mice tests, because there have been so many treatments that have led nowhere in people. Hundreds of cures in mice and (so far) no cures in people. However, the mice used in these tests were STZ mice, which I'm particularly nervous about. Basically, the researchers took healthy mice and injected them with a toxin (streptozotocin) which killed their beta cells. These are are referred to as STZ-mice. They are commonly used as an animal model of type-1 diabetes, however they do not have autoimmune diabetes. In comparison NOD-mice, also used as an animal model of type-1 diabetes, do have autoimmune diabetes.
In my opinion, STZ-mice are fine for testing new insulins and pumps, and also for doing tests related to long term complications. However, I don't think they are good models for testing cures, because they lack the ongoing autoimmune beta cell destruction which is the hallmark of real type-1 diabetes.
The danger is that even if Verapamil does cause the body to grow more beta cells, they will be destroyed by the autoimmune attack, and patients will not see any improvement. This treatment could be combined with something that stops the autoimmune attack, and the combination might be a cure, but testing Verapamil alone is unlikely to give good results. The researchers understand this; the interview with Dr. Anath Shalev makes that clear. Her hope is that by carefully measuring BGs (using a CGM) and C-peptides, she will see a small improvement, which will have good health effects (even if it is not a cure). My blog posting "The Value of a Few Beta Cells" discusses this point:
Also, a small improvement could provide the justification for a combination trial (Verapamil and an immune modulator/suppressor), and such a combination could be a cure in the future.
But in a certain sense, even discussing the mouse research is a waste of time, once the human trials have started. Only the human trial results will matter moving forward.
publicjoshualevy at gmail dot com
All the views expressed here are those of Joshua Levy, and nothing here is official JDRF or JDCA news, views, policies or opinions. My daughter has type-1 diabetes and participates in clinical trials, which might be discussed here. My blog contains a more complete non-conflict of interest statement. Thanks to everyone who helps with the blog.