Why Did Progesterone Show No Benefit In Stage III Clinical Trials For Traumatic Brain Injury?

[Nick]

Progesterone was very successful in treating traumatic brain injury in animal models and human clinical trials stages I & II but showed no effect at all in 2 large stage III trials. Stage I & II trials used, respectively, 1 and 2 mg/kg/day intravenously. The stage III trials both increased the intravenous dosage to 12mg/kg/day. It has been proposed that this 6x dose increase is responsible for eliminating the neuroprotective effect because progesterone may have a U-shaped dose response curve.
Ray Peat however seems to suggest that more progesterone is always more protective. Perhaps brain glycogen was depleted by the high dose but I have trouble believing that this alone would eliminate ALL protective effect.
Does anybody have any thoughts on why this would occur? This failure in clinical trials seems like a huge blow to the possible acceptance of a major use of progesterone by the mainstream medical system since there may not be any more attempted. I would really like to ask Ray what he thinks but I can't find his contact information.

Randy B. Howard, Iqbal Sayeed, Donald G. Stein. Suboptimal dosing parameters as possible factors in the negative Phase III clinical trials of progesterone for TBI. J Neurotrauma 2016. doi: 10.1089/neu.2015.4179

 

[schultz]

I have heard him say a few times that taking progesterone cyclically is better than constantly. I'm not sure how this would be relevant to head injury though. I would love to hear Ray's response if you ever get it.

 

[meatbag]

Progesterone was very successful in treating traumatic brain injury in animal models and human clinical trials stages I & II but showed no effect at all in 2 large stage III trials. Stage I & II trials used, respectively, 1 and 2 mg/kg/day intravenously. The stage III trials both increased the intravenous dosage to 12mg/kg/day. It has been proposed that this 6x dose increase is responsible for eliminating the neuroprotective effect because progesterone may have a U-shaped dose response curve.
Ray Peat however seems to suggest that more progesterone is always more protective. Perhaps brain glycogen was depleted by the high dose but I have trouble believing that this alone would eliminate ALL protective effect.
Does anybody have any thoughts on why this would occur? This failure in clinical trials seems like a huge blow to the possible acceptance of a major use of progesterone by the mainstream medical system since there may not be any more attempted. I would really like to ask Ray what he thinks but I can't find his contact information.

Randy B. Howard, Iqbal Sayeed, Donald G. Stein. Suboptimal dosing parameters as possible factors in the negative Phase III clinical trials of progesterone for TBI. J Neurotrauma 2016. doi: 10.1089/neu.2015.4179

He actually wrote a whole newsletter about it

 

[passivity]

@Nick
Could you PM the newsletter @Meatbag is talking about?

 

[dand]

He actually wrote a whole newsletter about it

What newsletter was this? Would love to read it. I have a subscription, but I don't recall this. Thanks.

 

[dand]

@haidut did you have any commentary here?

 

[Such_Saturation]

Maybe it's suppressing stress so much that the repair doesn't trigger?

 

[dand]

That's an interesting thought, but in the newsletter Ray takes this exact issue to task. He said that they were basically using PUFA as a solvent and that the PUFA counteracted the progesterone. In addition, it seems like they were using a really small amount of progesterone.

"When solid particles enter the blood circulation, they are likely to be trapped in the spleen. Ordinary "pharmacokinetic" studies measure the amount of a drug and its metabolites that appear in the urine, but I haven't seen evidence that this was done in these progesterone studies.

A common problem with prolonged intravenous infusion o f drugs is inflammation o f the veins. and the US study reported that the progesterone- intralipid solution caused phlebitis. The presence of crystals in an infused material can produce phlebitis.

The possibility that some of the progesterone wasn't reaching the patients' brains is a minor flaw of these studies. The real problem is that intralipid greatly increases free fatty acids in the blood, and free fatty acids, especially when they are polyun- saturated, are toxic to the brain, increasing inflam- mation and blocking energy metabolism. "

 

[meatbag]

That's an interesting thought, but in the newsletter Ray takes this exact issue to task. He said that they were basically using PUFA as a solvent and that the PUFA counteracted the progesterone. In addition, it seems like they were using a really small amount of progesterone.

"When solid particles enter the blood circulation, they are likely to be trapped in the spleen. Ordinary "pharmacokinetic" studies measure the amount of a drug and its metabolites that appear in the urine, but I haven't seen evidence that this was done in these progesterone studies.

A common problem with prolonged intravenous infusion o f drugs is inflammation o f the veins. and the US study reported that the progesterone- intralipid solution caused phlebitis. The presence of crystals in an infused material can produce phlebitis.

The possibility that some of the progesterone wasn't reaching the patients' brains is a minor flaw of these studies. The real problem is that intralipid greatly increases free fatty acids in the blood, and free fatty acids, especially when they are polyun- saturated, are toxic to the brain, increasing inflam- mation and blocking energy metabolism. "

also the progesterone crystallized of out solution before injection

 

[dand]

Exactly. Tis a crime. Thank god for Ray Peat and this forum.

 

[Seleniodine]

Looks like they mixed the progesterone with soybean oil! wtf?

Here is a link to the NEJM article about the study :

Very Early Administration of Progesterone for Acute Traumatic Brain Injury

"Site pharmacists prepared the coded kit assigned by the randomization algorithm by mixing a weight-based dose (0.05 mg of progesterone per kilogram of body weight per milliliter of infusate) from the provided vials and a 250-ml bag of fat-emulsion vehicle (Intralipid 20%, Fresenius Kabi) every 24 hours."

Intralipid® 20%A 20% I.V. Fat Emulsion In Excel® Container

"Intralipid® 20% (A 20% I.V. Fat Emulsion) Pharmacy Bulk Package is a sterile, non-pyrogenic fat emulsion intended as a source of calories and essential fatty acids for use in a pharmacy admixture program. It is made up of 20% Soybean Oil, 1.2% Egg Yolk Phospholipids, 2.25% Glycerin, and Water for Injection. In addition, sodium hydroxide has been added to adjust the pH so that the final product pH is 8. pH range is 6 to 8.9."

On this page Progesterone for the Treatment of Traumatic Brain Injury III - Full Text View - ClinicalTrials.gov about the study at the bottom of the page they mention under ;

"Additional relevant MeSH terms:

Wounds and Injuries
Brain Injuries
Brain Injuries, Traumatic
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Progesterone
Soybean oil, phospholipid emulsion
Progestins
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Fat Emulsions, Intravenous
Parenteral Nutrition Solutions
Pharmaceutical Solutions "

So did they even use natural progesterone or some form of progestin?

 

[haidut]

Exactly. Tis a crime. Thank god for Ray Peat and this forum.

Seems like you already found the answer. Also, I would have tried progesterone in DMSO. Despite the hysteria against DMSO around here, it would get most of the progesterone in the brain regardless of whether these people had had FFA, inflammation, compromised BBB (which many of them do) or fast second-phase metabolism. Most of the animals studies which noted benefit used progesterone dissolved in DMSO. Why weren't the human trials designed the same way, even if for no other reason by to replicate as closely as possible the animal trials?? Once the benefit has been confirmed then is the time to seek for other solvents, if needed at all. So many of these trials with bioidentical hormones are designed to fail from the start or are at least done with the attitude of " we will replace this working this with another thing which our provably correct theory says MUST work the same way". Except when it doesn't.

 

[Dhair]

Seems like you already found the answer. Also, I would have tried progesterone in DMSO. Despite the hysteria against DMSO around here, it would get most of the progesterone in the brain regardless of whether these people had had FFA, inflammation, compromised BBB (which many of them do) or fast second-phase metabolism. Most of the animals studies which noted benefit used progesterone dissolved in DMSO. Why weren't the human trials designed the same way, even if for no other reason by to replicate as closely as possible the animal trials?? Once the benefit has been confirmed then is the time to seek for other solvents, if needed at all. So many of these trials with bioidentical hormones are designed to fail from the start or are at least done with the attitude of " we will replace this working this with another thing which our provably correct theory says MUST work the same way". Except when it doesn't.

Speaking of DMSO - are you still considering bringing it back as a third solvent option?

 

[haidut]

Speaking of DMSO - are you still considering bringing it back as a third solvent option?

Yes, but have to get some more votes for it. So far, maybe only about 20 people have asked for it to be brought back.

 

[Dhair]

Yes, but have to get some more votes for it. So far, maybe only about 20 people have asked for it to be brought back.

Add me to the list. I was always on the fence with DMSO, but I have turned the corner on it a bit. I do feel that the SFA esters are less potent (especially thyroid), and due to Peat's comments and my own experience, I do not think it's safe to put SFA esters products on the scrotum. Makes me feel ill and messes things up down there. Anyway, not trying to hijack the thread, just wanted to make my thoughts known.

 

[haidut]

Add me to the list. I was always on the fence with DMSO, but I have turned the corner on it a bit. I do feel that the SFA esters are less potent (especially thyroid), and due to Peat's comments and my own experience, I do not think it's safe to put SFA esters products on the scrotum. Makes me feel ill and messes things up down there. Anyway, not trying to hijack the thread, just wanted to make my thoughts known.

OK, thanks for the vote. Btw, the SFA esters should not mess things up down there. The amount of those esters in just 3-4 drops is so tiny it will probably bet metabolized in the skin before it manages to affect the gonads.

 

[morgan#1]

I would like/love dmso! I had a car accident 15 yrs ago. The doctors did an evacuation of the blood pooling in my brain, craniotomy; left frontal lobe is damaged. It sounds like I would benefit from dmso, especially progesterone induced. 2 c. Thanks

 

[Mito]

The efficacy of progesterone 1 mg kg -1 every 12 hours over 5 days in moderate-to-severe traumatic brain injury: A meta-analysis of randomized controlled trials - PubMed

Conclusions: We conclude that PG, at a dose of 1.0 mg kg-1 via intramuscular injection every 12 h for 5 consecutive days, could significantly improve GFO (1 month, 3 months, 6 months, and 12 months) and reduce the medium-term (3-month and 6-month) mortality rate. Larger studies are needed to support our findings.

The efficacy of progesterone 1 mg kg -1 every 12 hours over 5 days in moderate-to-severe traumatic brain injury: A meta-analysis of randomized controlled trials - PubMed

 

[ken]

I had been checking the trials website every few months looking for updates on that trial. So when I found it ended I emailed Ray that night. He called the lead investigator the next day. I don't remember if this was in a email or the newsletter, that it really wasn't a test of progesterone but the delivery system which was the property of the Pharma company which paid for trial.

 

[Lollipop2]

I had been checking the trials website every few months looking for updates on that trial. So when I found it ended I emailed Ray that night. He called the lead investigator the next day. I don't remember if this was in a email or the newsletter, that it really wasn't a test of progesterone but the delivery system which was the property of the Pharma company which paid for trial.

Fascinating. Thank you for this follow up.