[jeanb]

When there is invasive brain surgery - as in the Ceregene trial for the participants who got the real treatment, would those participants have a different, more severe case of facial swelling than the participants who had "sham - the burr hole" surgery? And would the participants who got the real treatment (i.e. invasive surgery) have other different, and more severe reactions after the surgery?

I don't have any facts one way or the other, but I think this is a question that researchers should honestly answer.

Because if my supposition is correct - that physical reaction after sham brain surgery is different from invasive brain surgery, then having sham brain surgery doesnt produce a truly "blind" trial. And that would be a BIG reason to rethink and hopefully stop this sham surgery business.

[pegleg]

Jean - your question came up in our other forum on clinical trials - "CERE-120 The Story". I have copied my response below:

I had brain surgery and was not told to "expect" swelling (and I was in an open label study; i.e. I knew I was getting the real thing.) To say this would probably unblind the placebo group almost immediately. And for the most part I didn't have much swelling; I imagine the amount of swelling would be determined by how much trauma was inflicted to the brain.

There was a puffy kind of look on my eyelids (which several have said is indicative of brain surgery). It was like my eyelids became thin and fleshy and seemed to pile up on my lashes. Of course the doctors and nurses caring for these patients would recognize the post-op appearance of one who has had brain surgery, but they have been trained accordingly. Only the neurosurgeon would know.

I also know that each patient's response to any type of surgery varies greatly. For example, after my surgery (Spheramine) there was an overnight stay in ICU (Intensive Care Unit) built into the protocol. I recall awakening in the recovery room awaitingn my transfer to ICU. However, I had this euphoric feeling (an almost "I'm cured!" feeling that lasted for about 2 weeks). I was very talkative and remember telling the male nurse in recovery every clean or semi-clean joke I knew. About a half hour later, I saw him on the telephone with his back to me, obviously trying to hide his conversation from me. He was talking with the neurosurgeon (I found out after he hung up). And this is what he said, "I CAN'T sewnd her to ICU! She's sitting up telling jokes!" So I went straight to the regular room, where I stayed for 3 days.

I recall wondering why my movement disorder specialist didn't visit me (the research nurse did, but it was on the day of discharge when swelling was minimal). In retrospect it must have been because he would have recognized the swelling or "fleshy" eyelids and the study would have been unblinded.

But Jean, this means the bedside caregivers, and in this case POSSIBLY the research nurse, would recognize the after effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura). That is putting a lot of trust into those people, some even non-professionals. So there is a big chance someone might leak those receiving the real therapy, even unknowingly. Therefore, this is even more reason to add to taking a long look at the validity of using sham surgery.

Peggy

[jeanb]

If the after-effect of actual penetration of the brain's dura (in sham surgery, they drill the hole, but don't penetrate the dura) is different from the after-effect of true invasive brain surgery, then how can researchers claim the study is blind?

This question must be pursued because in my opinion, if it turns out to be true, then it is a big strike against using sham surgery.

[girija]

Good morning!

All the talk about placebos, appropriate controls and FDA rules, made me look back into my folders about a gene therapy clinical trial I was familiar with. It was gene therapy for haemophilia by providing factor VIII using a gutted-adenoviral vector. It was in 2002 and was one of the first few gene therapy trials with adenoviral vectors. This FDA and RAC approved clinaical trial protocol had no placebo controls to compare with. It was assyaing for factor VIII before and after treatment . It was a Phase 1, and the end point was detectable factor VIII and of course the safety issue that is associated with using adenoviral vector. My involvement in this trial was minimal, and do not have many required details and thats why I hesitated to post it here. But it might be useful info to know that FDA did approve a gene therapy protocol without an appropriate, untreated/vector alone group. It all depended on how the protocol was written and justified to the FDA.
Thanks
Girija

[paula_w]

Someone needs to correct me big time if this isn't correct, but I don't think it's written anywhere that a placebo is required for clinical trials. It's just a practice that the FDA requires...an unwritten "law"?

Girija, are you saying that there was a gene therapy trial with no placebo required?


thanks,
paula

[girija]

Paula,
yes, thats what I am saying based on the information I have. Like I said , my role in that project was minimal and I do not have all the details. As I recall, there were only three patients for that study. It might have been a special consideration case. I will try to find out more from my collegues and post it .
Girija

[jeanb]

thanks Girija,

Very interesting!!

[girija]

hi all,
here is a bit more info, so far, it seems like there was no placebo group for this gene therapy trial

"A phase I study of a fully deleted adenoviral vector for hemophilia A is now in late planning stages. The trial is sponsored by the Genstar Corporation and is structured as an open-label dose-escalation study, with 3 subjects in each of 3 dose cohorts. Vector is to be infused intravenously at doses ranging from 4.3x1010 vector particles (vp)/kg to 4.3x1011 vp/kg."

taken from
Circulation Research. 2001;88:137-144

Right arrow Genetics of cardiovascular disease
(Circulation Research. 2001;88:137.)
© 2001 American Heart Association, Inc.
Review
Gene Transfer as an Approach to Treating Hemophilia
Katherine A. High

From the University of Pennsylvania School of Medicine and Hematology Division, The Children’s Hospital of Philadelphia, Philadelphia, Pa.

Correspondence to Katherine A. High, MD, The Children’s Hospital of Philadelphia, 3516 Civic Center Blvd, 310 Abramson Research Center, Philadelphia, PA 19104.

[girija]

THis is an interesting article.
Check it out!

Hróbjartsson A, Gøtzsche PC. Is the placebo powerless? An analysis of clinical trials comparing placebo with no treatment. N Engl J Med May 24, 2001;344:1594-602.

Summary at the end of the paper says it all.

"When the data from each of the trials were pooled, there was no evidence of a beneficial effect of placebo in studies with binary outcomes, or in continuous outcome trials that used objective scoring criteria. There was a positive effect for placebo in continuous outcome trials with subjective assessment criteria (especially treatment of chronic pain), but this effect diminished with increasing sample size, leading the authors to suspect biased assessment in smaller, subjective studies.

The authors conclude that there was no obvious beneficial effect to placebo versus no treatment, and discouraged the use of placebo treatment outside the setting of a controlled clinical trial."

[paula_w]

Yes it's most interesting girija. we all need to look at this. it affects everyone.

paula