Björn Vrooman Aug 12, 2014:

continued Now, can anyone say for sure what the “follow-up” refers to?

But why focus on the follow-up? Because a lot of studies I’ve found exclude anyone who has recently participated in another study and taken a certain drug for a period of between, say, 30 days and a few months before the new screening – that matches the period of the possible follow-up quite well but not the entire trial period of 12 months.

In fact, I can’t seem to find a single(!) reference supporting the statement that placebos are classified as off-treatment (they also have on- and off-treatment periods):

“compared to placebo during the on-treatment period“
http://www.ncbi.nlm.nih.gov/pubmed/24718923

“In the year off treatment, spine BMD decreased significantly, but remained higher than baseline [...] and placebo [...]”
http://www.uptodate.com/contents/the-use-of-bisphosphonates-...

“Patients on placebo showed no difference in OT […] on and off treatment.”
http://www.ncbi.nlm.nih.gov/pubmed/24676931

“The 2 mL and 3 mL placebo treatment groups”
https://www.clinicaltrialsregister.eu/ctr-search/trial/2009-...

Who knows what the entire text says.

Björn Vrooman Aug 12, 2014:

Follow-up on follow-up My guess is based on the Pulmaquin case below. Patients can decide whether they want to take part in an open label extension (could be included in the double-blind trial) or not:

"patients participating in double blind placebo controlled trials of new medications are invited, on completion of the initial trial, to take the study drug for some further period."
http://jme.bmj.com/content/28/6/373.full

“In the open-label period (including safety follow-up)”
http://www.lundbeck.com/upload/trials/files/pdf/completed/10...

“Patients who completed the 12-week double-blind treatment period were proposed to participate in the open label period [during the follow-up period, I’d say] with eplivanserin 5 mg for an additional 40 weeks”
http://en.sanofi.com/img/content/study/LTE6262_summary.pdf

“A follow up open label study examined extended courses of etanercept in the same group of patients with AS, with the aim of “
http://ard.bmj.com/content/64/11/1557.full.pdf

“During a four-week double-blind sham-controlled phase and a subsequent 11-month follow-up open label period”
http://juser.fz-juelich.de/record/153725/?ln=de

Björn Vrooman Aug 11, 2014:

@Charles and Donal Thank you for the comments! I agree that it may not be possible to resolve this issue without the asker's input - I simply do not want to focus only on trial or period when looking for the bigger picture.

Otherwise, the asker may end up not seeing the forest for the trees.

Björn Vrooman Aug 11, 2014:

@Tony "I think you may be missing the point slightly: in the field of clinical trials (where comparative studies are involved) the specialist terms 'on-treatment' and 'off-treatment' are used to refer to those patients who are receiving the active treatment, as distinct from (say) the placebo. "

I've found sources to the contrary. Another one:
"Patients are randomized to receive either rhNGF at one of two doses or placebo, administered subcutaneously twice weekly for 18 weeks. Patients are stratified into three groups within their regimens by use of didanosine, zalcitabine, or stavudine as follows: current use vs. discontinued between 8 and 26 weeks before randomization vs. never used or discontinued use at least 26 weeks before randomization. Patients will assess their pain daily using the Gracely Pain Scale. AS PER AMENDMENT 5/6/97: After completion of the double-blind phase (18 weeks on treatment followed by 4 weeks off treatment), patients may receive open-label, active drug treatment according to their previously assigned regimen for an additional 48 weeks."
http://clinicaltrials.gov/show/NCT00000842

Off- and on-treatment refer to the same group, not two.

Tina Vonhof (X) Aug 11, 2014:

@Tony Since it is a double-blind trial, 'treatment' may mean either treatment with the study drug or treatment with a placebo. No one knows who gets what. That may be known only during the post-treatment period.

Charles Davis Aug 11, 2014:

I tend to agree with Donal here. I don't think this can be definitively resolved. I will admit that I am rather more willing to entertain the possibility that "this" refers to the follow-up (which is, after all, the nearest noun) than I was before Björn posted his material.

Tina Vonhof (X) Aug 11, 2014:

I think that 'this' must refer to the follow-up, because post-treatment means that the patient was receiving treatment before the follow-up, and only during the follow-up could he/she then be off-treatment. The patient cannot have been off-treatment at any time during the trial or or during the 12 months before the follow-up.

DLyons Aug 11, 2014:

@Björn I think the asker is the only person who may have enough information about the trial protocols to be able to answer the question. I posted my own initial reaction in a discussion entry, but that's no more than an instinct.

Björn Vrooman Aug 11, 2014:

@Charles, Donal, and Tony I would really appreciate any replies based on the reference(s) provided below, especially because they seem to support Donal's earlier statement.

I'd rather read: "irrespective of whether the subjects were on or off treatment during the follow-up/after completion and transfer"

instead of

"irrespective of whether the subjects were on or off treatment during the 12 months/the trial"

The second still sounds to me as if the "subjects" possibly didn't receive any treatment at all - and I am sure that was not the case during trial XXX.

Björn Vrooman Aug 11, 2014:

@B D Finch Don't know where you get the drop-out from? The text clearly says: Completed and transferred. You are required to have completed this stage - otherwise, you will not be admitted to the next trial. Nothing else. I highly doubt that off-treatment has anything to do with dropping out. See also my references below.

Consider: If someone dropped out, he or she would not be eligible anyway because of the non-completion of trial XXX. So why would I need another explanation in brackets?

To your second point: Yes, of course, thank you, I edited it. My mind must be wandering off...

B D Finch Aug 11, 2014:

@Bjorn Referring to the entire 12 months makes a great deal of sense because people do drop out of trials and people who dropped out before the 12 months was up would not be eligible for screening into the new trial.

Incidentally, re pronoun use: This (her painting her house pink) upset the neighbours.

Björn Vrooman Aug 11, 2014:

continued... I'd go for "irrespective of whether the subjects were on or off treatment when they completed and transferred from trial XXX" or "irrespective of whether the subjects were on or off treatment during the follow-up" - just my two cents. Referring to the entire 12 months makes no sense because they did get treatment (and if it was only placebos), and the same goes for the trial. It may make sense in case of the follow-up.

Interested what others think.

Björn Vrooman Aug 11, 2014:

Reference I've found a reference:
"Each trial will enroll approximately 255 patients into a 48 week double blind period consisting of 6 cycles of 28 days on treatment with Pulmaquin or placebo plus 28 days off treatment, followed by a 28 day open label extension in which all participants will receive Pulmaquin (total treatment duration approximately one year)."
http://www.businesswire.com/news/home/20140430005538/en/Arad...

And further:
"Open label extension studies typically follow a double blind randomised placebo controlled trial of a new drug. At the end of the double blind phase, participants are invited to enrol in an extension study. The study will normally be longer than the randomised trial (two years is not uncommon but they often continue until the drug is licensed). All participants in the extension study are given the study drug, and both they and the investigators know this. The objective is primarily to gather information about safety and tolerability of the new drug in long term, day to day use."
http://www.bmj.com/content/331/7516/572

Thus, I'd say "this" refers to the verbs (completion + transfer) or "follow-up".

Björn Vrooman Aug 11, 2014:

continued I like your suggestion. I don't understand sometimes why people cannot just be unambiguous - that would make everyone's job easier. I just thought "this" here would refer to "this action/situation" as it is a list item because the trial being off-/on-treatment doesn't make sense to me either.

Note to your reply: Wouldn't it be "on treatment" without a hyphen then? That definitely threw me off.

Björn Vrooman Aug 11, 2014:

@Tony Just a thought, especially considering Terry's objection that neither a period, nor a trial can be on-/off-treatment. But if you refer it to the entire list item: they completed and transferred from trial xxx, then the subjects are there again with on-/off-treatment.

Björn Vrooman Aug 11, 2014:

@all Anyone thought about "this" referring to "completed and transferred"?

A) "This" can refer to actions: She painted her house pink. This (her painting her house pink) upset the neighbors.

B) It's a list item (note the colon!)

C) Meaning: regardless of whether they completed and transferred from trial XXX off-treatment or on-treatment

Any thoughts on this (pardon the pun)? Wouldn't that make more sense?

In the same vein, the 12-month period may refer to the completion and transfer, not just the trial. Thank you!

Charles Davis Aug 11, 2014:

On-treatment and off-treatment are standard terms referring to persons who respectively do and do not receive the assigned study treatment during a trial. Off-treatment persons certainly do (at least sometimes) receive follow-up; if you think about it, this is necessary.

I think this is inaccurately expressed, and that, as Tony suggests, "post-treatment follow-up" really means "post-trial follow up".

The meaning is effectively the same whether we interpret "this" as referring to the trial or the twelve-month period; effectively these two denote the same thing, and that is what it refers to.

DLyons Aug 11, 2014:

@Tony I was envisaging the follow-up applying to all patients. But the devil is in the details, only the context can determine exactly what the follow-up consisted of.

DLyons Aug 11, 2014:

Conceivably In a clinical trial, during follow-up a randomised treatment could well be continued for both an active treatment group and a placebo group. In that case "this" would refer to the "post‑treatment follow-up".

Admittedly, it's a bit of a stretch to refer to a period of continuing treatment as "post‑treatment follow-up". But I could imagine a Statistician who was having a bad hair day, doing just that :-)

The context will probably rule this out!

B D Finch Aug 11, 2014:

@David Not exactly. Both phrases within the brackets are giving information about what completion of Trial XXX entails: completion requires completing a "12-month period including post‑treatment follow-up" and it is accepted that the subjects completed the trial whether they were "on-treatment or off-treatment".

David Moore (X) Aug 11, 2014:

Since this is not a specialist field of mine, I can only say it SHOULD refer to the '12-month period including post‑treatment follow-up'.

Whether this does in fact make sense in the wider context or not I don't know, and suggest you wait until confirmation from a specialist in the clinical trials field.,