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TOPIC: Thought On OA 12 Week Primary Endpoint

Thought On OA 12 Week Primary Endpoint 17 Jun 2015 07:59 #4679

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I've been kicking around an idea about the timing of the release of the OA trial primary endpoint. The primary endpoint looks extremely achievable given what we know about the anti-inflammation effect of ADRCs. If you recall this quote from Dr. Dizon from the Phillipines in my SA article:

Dizon: With regards to my own experience, I sustained a fracture of my left shoulder (glenoid bone) in a freak road bike accident last July 4, 2013. I did not get an operation right away as I was afraid to. I broke my glenoid into 3 separate pieces. After 4 weeks, I decided to have it repaired arthroscopically by my colleagues. Unfortunately, when they were trying to pin one of the small pieces, the fragment was shattered. So they just tried to repair the soft tissues that were damaged since they can't do anything anymore with my bone. In short, the surgery was not successful. They were supposed to do a 2nd operation to reconstruct the missing part by harvesting from my iliac crest and transplanting it but we decided to suspend it first. I did my rehab for more than 2 months 3x/week. After the operation, my arm was very weak and there's always pain from my shoulder and the whole left arm every time I tried to raise it. After more than 2 months of rehab, I was only able to raise it shoulder high and it was very painful as well as very weak beyond that. In October, after we did some cases with Dr. Cohen, he operated on me and injected ADRCs intra-articularly on my shoulder joint as well as intramuscularly on the surrounding muscles. 2 days after the procedure, I was able to raise my arm straight above my head with very little pain and with much strength. Now, 3 months after the procedure, there is still little pain and a feeling of tightness but the range of motion and strength are already almost full. My colleagues who operated on me are telling me it must be the soft tissue imbrication that they did that is causing the residual feeling. Overall, I feel so much better and I'm back to my normal activities. I had a baseline MRI and 3D CT Scan taken before the cell therapy and I plan to repeat these after 3 more months to compare them to the initial ones.



What I find interesting about this trial is that the primary endpoint, pain on walking, is measured at only 12 weeks All the secondary endpoints are at 48 weeks as follows:

Observed Pain Scores on 50-foot Walk Test [ Time Frame: 48 Weeks ]
Number of Observed OARS130 Responders [ Time Frame: 48 Weeks ]
Knee Injury and Osteoarthritis Outcome Score (KOOS) [ Time Frame: 48 Weeks ]
VAS Assessments [ Time Frame: 48 Weeks ]
Patient Global Assessment [ Time Frame: 48 Weeks ]
Use of Rescue Medication [ Time Frame: 48 Weeks ]
SF-36 Questionnaire [ Time Frame: 48 Weeks ]
MRI Osteoarthritis Knee Score [ Time Frame: 48 Weeks ]

So this is the question: Will the primary endpoint at 12 weeks be known by Cytori before the 48 day data has been collected?. And if it is successful, can the primary endpoint results be published early. My guess is it may be known but cannot be published but I am not clear on this. The key question, if 12 week data is published but the patients and investigators remain blinded as to their own therapy (placebo vs. treated) does the mere fact that primary endpoint was met taint the results of the secondary endpoints?
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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 09:52 #4680

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So this is the question: Will the primary endpoint at 12 weeks be known by Cytori before the 48 day data has been collected?.


Good question, but from my experience as long as the trial is not completed on all primary and secondary endpoints, the whole population remains blinded for everyone, including the clinic Steering Board. Of course- it always is possible that PI´s "see through the blinding" due to sharply contrasting results, but that will likely remain anecdotal and non-scientific.

At 48 weeks- Knee Injury and Osteoarthritis Outcome Score (KOOS) - Pain on Walking- is an endpoint also and key surely will be to compare 12 with 48 weeks.

In the Manilla story that you wrote, it amazes all the time how fast that can work- the OA clinic from Cellthera, which was an "open study", also showed fast results....

After 3 months from SVF therapy, at least 50% clinical improvement was recognized in 95%, at least 75% clinical improvement in 68%, and complete remission in 54% of patients, respectively. Within 1-2 weeks from SVF therapy 85% of patients were off the non-steroid analgesics and remain such for at least 6 months. No serious side effects, infection or cancer was associated with SVF cell therapy. In conclusion, here we report a novel and promising therapeutical approach that is safe, cost effective, and relying only on autologous cells.

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 11:36 #4681

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If we consider a 48 week timeframe for all data this statement from the PR seems impossible to meet.

>>>The availability of safety and efficacy data in Q1 2016 will lead to informed decisions and discussions with the FDA regarding the study design and size of an osteoarthritis Phase III program with Cytori Cell Therapy.<<<

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 14:57 #4683

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Good point Hedge.

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 15:26 #4684

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Really interesting topic - because at the end of the day these are things that really matter, i.e. successful trials.

Official Link: https://clinicaltrials.gov/ct2/show/NCT02326961

Just the status needs to be updated as enrollment completed :nice:

For the next months I would really be pleased if we could avoid a r/s... with good data and avoiding foolish mistakes my humble goal would be to be back at around 5 bucks in 5 years...

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 18:48 #4685

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SAN DIEGO--(BUSINESS WIRE)-- Cytori Therapeutics (NASDAQ: CYTX) announced today that enrollment has been completed in its US Phase IIb Osteoarthritis trial. The ACT-OA trial is a double-blind randomized, placebo-controlled trial evaluating the safety, feasibility and dosing of intraarticular administration of Cytori’s ECCO-50 cellular therapeutic in patients with knee osteoarthritis. A total of 94 patients were enrolled as of June 12, 2015.

“Based on faster than anticipated enrollment, we now expect to have six month follow up data for review in Q1 2016. We are very encouraged by the rate of recruitment, which was completed months ahead of the original plan,” said Marc Hedrick, CEO and President, Cytori Therapeutics. “Based on 24 week follow-up outcomes, we will provide an update on the data and the Phase 3 design, including the size of the trial, cost and end points."

WST and Fas: I see no reference to a 48 week study. Where did 48 weeks come into play?

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 20:26 #4686

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Follow the clinicaltrials.gov link provided by Lugano on this thread.

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Thought On OA 12 Week Primary Endpoint 17 Jun 2015 21:44 #4687

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We have all seen where the 24 week and 48 week evaluation points are mentioned. There does appear to be a bit of a confusion which can easily be rectified by posing a simple question to the company.

The primary endpoint is 12 weeks so it is only rational that the data collection for the 12 week analysis be done promptly at the end of that period. The data collection would be undertaken by the Primary Investigators but would be analysed and assessed by an independent reviewer. The active participants would continue to be blinded.

This is a Phase II trial and Cytori is not going to ask for approval on the basis of this single trial. There is no statistical penalty for an early look. It is entirely reasonable to have a 24 week review, which from the company's point of view is critical given its limited financial resources. It will give it a good heads up so it can start to work on an expanded trial and liaise with the FDA quicker than would otherwise be possible.

As for the 48 week data it would give vital information concerning the duration of the treatment effect.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 07:28 #4689

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It is entirely reasonable to have a 24 week review, which from the company's point of view is critical given its limited financial resources. It will give it a good heads up so it can start to work on an expanded trial and liaise with the FDA quicker than would otherwise be possible.


John- a 24 week review is nowhere mentioned on the record for ACT-OA at clinicaltrials.gov. I know that does not say much, since we know keeping track of information things for the public, which includes shareholders has NEVER been Cytori´s strength. :whistle: :puke:

I presume really the study lay-out is simply 24 weeks now and the 48 weeks is totally SCRAPPED, since we should not forget one thing... :whistle:

THE PATIENT ALWAYS SHOULD COME FIRST!!

If results are released on 24 weeks, you cannot expect patients to wait another 6 months with a ringer solution in their knee instead of their own cells :evil: :evil: :evil: ... they should be allowed- at least with a phase II- to swop to real thing ASAP.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 08:29 #4690

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>>>I presume really the study lay-out is simply 24 weeks now and the 48 weeks is totally SCRAPPED<<<

I was wondering the same thing Fas.
Communication still a major issue at Cytori !!!! :cry: :KO: :evil:

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 09:32 #4692

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Before we get further into this discussion we need to know for sure what the time frames are for the evaluation points. I left a message for Tiago to calrify. Why the press release would not be consistent with the listing on clinicaltrials.gov is puzzling.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 13:45 #4693

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From Cytori:

The interim analysis will be conducted when all subjects have completed 24 weeks. The purpose of the interim analysis is to enable an initial review of the safety and feasibility so that we can plan for the next phase of the clinical development program. The following endpoints will be analyzed in the interim analysis:

KOOS pain on walking question
Observed pain scores on 50-Foot walk test
KOOS subscales
VAS assessment
Patient global assessment
Average number of tablets/capsules of rescue medication per week
Adverse events, serious adverse events, and unanticipated adverse device effects.

While the primary endpoint (KOOS pain on walking question) is specified for testing at 12 weeks, it is measured at other times. Clinically, it is perhaps most relevant to see a change in pain by 12 weeks; however, it is also critical to examine for sustained improvement in which case 24 week assessment is needed. Perhaps more importantly, we need to evaluate multiple endpoints to examine for consistency and associated expected benefits (such as improvement in ability to participate in physical activities).

Potential bias is introduced by early evaluations and therefore undesirable to examine data at 12 weeks. The time difference in availability of analysis is between 2 and 3 months. Given the time difference (minor), the benefits of not introducing bias outweigh the downside. Hence the decision to look at interim data only at 6 months. We will also look at final data at 12 months.
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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 14:33 #4694

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Anybody gets this in relation to "treatment versus control"?

I dont. :whistle: Anyway- they should get the Clinicaltrials.gov record straight. maybe that helps.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 14:58 #4695

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I don't think I understand your question, Fas, There are three groups: Low Dose, High Dose and Placebo. I think you know this so what exactly are you asking?

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 14:59 #4696

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Thanks WST.
Sounds to me like they changed from 12 to 24 weeks for the interm look.
Also final data will be at 12 months ( I assume instead of 48 weeks ?.)

Fas
Looks like all 3 groups will be in for a 12 month haul with this trial

PS
Every look has the effect as a notch against you towards data validity so that is why there will be no 12 week look along with the 24wk and 12 month.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 15:34 #4697

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Hedge, the way I read this, the primary endpoint is still at 12 weeks. However, the Interim look at 24 weeks will not reveal whether the 12 week primary endpoint has been achieved even though the 24 week data will be revealed at 6 months. As stated in the email to me: "The purpose of the interim analysis is to enable an initial review of the safety and feasibility so that we can plan for the next phase of the clinical development program." Planning for the next Phase is only feasible if the interim data are solid.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 15:51 #4698

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I don't think I understand your question, Fas, There are three groups: Low Dose, High Dose and Placebo. I think you know this so what exactly are you asking?


The groups are clear. Cytori wants to check safety - OK- the usual bit, but also feasibility at 24 weeks. You check feasibility by comparing the two treatment groups with the control group in order to see the benefit i.e. unblind the groups and everybody knows who got treated and who did not.

After that patients most probably give answers to questionnaires and other "soft data" based on their knowledge whether they were treated or not- so 48 weeks data will be pretty useless.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 16:02 #4699

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If the 24 week data is revealed at 6 months as stated above, then the 48 week secondary endpoints have already been collected while everyone was still blinded.

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 16:25 #4700

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If the 24 week data is revealed at 6 months as stated above, then the 48 week secondary endpoints have already been collected while everyone was still blinded.


Does not make sense to me. Last patient was enrolled on June 12 2015, so 48 weeks review will take place for that patient early May, whilst 24 weeks data is published in Q1 2016?? :whistle:

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Thought On OA 12 Week Primary Endpoint 18 Jun 2015 17:21 #4701

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So you are saying they are collecting data at 12 weeks,. 24 weeks and 48 weeks or maybe they will collect it at 12 months because what's another 4 weeks from 48 ?

Why is it IMPOSSIBLE for this company to be clear about anything ?!?!?!!!!!!! :bash:

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