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The preliminary results from the K Pax Synergy trial are in. Run at four centers across the country, this  placebo-controlled, double-blinded 120 person trial combined a central nervous system stimulant (methyphenidate/Ritalin) with a nutrient formula. The idea was that as the stimulant boosted central nervous system activity the nutrient formula would enhance mitochondrial and immune functioning and protect against side effects. Dr. Kaiser, the originator of the Synergy formula, believes mitochondrial dysfunction plays a key role in ME/CFS.

_Clinical-Trial-1222848Good-sized placebo controlled, double-blinded studies don’t come around very often in chronic  fatigue syndrome. Nor are hopes usually as high as they were for this one. Reports of some patients fantastic results – one long time disabled patient going back to work comes to mind – piqued  considerable interest about the trial.

This “phase-two” treatment trial was designed to determine if the combination formula was safe and efficacious, and to inform the team how to best produce a possible, much larger, phase-three trial.

Results

The patients in the placebo arm of the Synergy trial averaged a 13% decline in their Checklist Individual Strength (CIS) scores. The patients taking the Synergy formula averaged 22% decline in their CIS scores.  The difference between the two did not have statistical significance. In the FDA’s eyes the study would have been a failure.

But what does a 22% decline in a CIS score mean for a patient? The average beginning CIS score was about 110. A 22% decline in that score would put a patient at about 88.  Seventy-six is considered the cutoff point for remaining in the workforce. Go above 76 and you’re probably going to drop out of the workforce. Go below 76 and you’re probably going to stay in the workforce.

The average response didn’t put the “average” patient back into the workforce but it put them within about 10 points of possibly entering it. That indicates that a significant increase in functionality occurred.

Nor does the overall result say anything about the really positive responders. I asked Dr. Kaiser if anyone had a response similar to that of the disabled woman who was able to return to the workforce. He said about 10-15 people had responses like that. That’s about 20% of those getting the drug.

Relativity Strikes: High Placebo Response Complicates Findings

The large amount of  patients in the placebo arm with a very positive placebo response complicated the results. Dr. Kaiser said ten to fifteen of the patients had high enough placebo responses to, by the measures of the study, be considered cured.

  • 01-007         -27 point decline
  • 01-018         -39 point decline
  • 01-056         -60 point decline
  • 01-070         -62 point decline
  • 02-035         -47 point decline
  • 02-038         -30 point decline
  • 03-019         -68 point decline
  • 03-028         -48 point decline
  • 03-029         -83 point decline
  • 04-003         -84 point decline

Because the most important results of the trial for the FDA involve the difference between the placebo and the treatment arm responses, the high placebo responses found were problematic.

I asked Dr. Kaiser if he thought high expectations played a role? That was one possibility.  A statistical anomaly was another; it may be the Synergy group just happened to bump into some patients with very high placebo response rates.

Choices

One result suggested the trials was successful; the other – the one FDA relies on – suggested it wasn’t

The two methylphenidate studies highlight what complicated beasts clinical trials can be. They indicate that a drug that provides less benefit to the patients but has a lower placebo response rate could be considered a success by the FDA. A drug  that provides more benefits to the patients, on the other hand, but also has a higher placebo response rate could be considered a failure.

In the 2006 methylphenidate trial the ME/CFS patients responded less well (11% improvement) than in the Synergy trial, but the low placebo response (3% improvement) in the 2006 trial made the drug look more effective than it was. The difference between the two allowed the authors to say:

Methylphenidate at a dose of 2 x 10 mg/day is significantly better than placebo in relieving fatigue and concentration disturbances in …. chronic fatigue syndrome patients.

The placebo response in that trial (3%) was so low that the trial ended up shining in the measure the FDA considers most important. In that trial only 17% of the patients were considered to have a clinically significant response.

Such are the vagaries of clinical trials. I tend to hold my breath when clinical trial results are announced. I don’t particularly trust them  – by which I mean I wouldn’t choose or not choose a drug based solely on them.

I expect the positive effects of good drugs to be washed out to some extent by the different types of patients in the trial. The high degree of heterogeneity present in the ME/CFS population, after all, is a known barrier to drug development. Drug companies are reluctant to invest in a drug that gets tested in a group of ME/CFS patients. They’re afraid even a good drug will not get the results they need to get FDA approval. In this case that appeared to be true.

I vividly remember Dr. Klimas exclaiming that if they’d just chosen a different endpoint to measure, one trial would have been a success. Instead, the trial was considered a failure.

Additive Effects?

KPAX ResponseThe patients in the placebo arm got better at first and then started to worsen as the placebo effect wore off. The patients in the K Pax arm, however, continued to improve from week four to week 12. We usually think of a drug as having the same effects over time, but nutrient addition in the Synergy trial added a different component. I asked Dr. Kaiser if nutrients could be more effective over time as they continue to strengthen the body. He thought yes.

He also suggested that the increased ability of the responders to participate in the normal activities of life could help explain the increasing benefits of the formula over time. Clinical trials do not always produce black and white results.

A Safe Combination

The KPAX 002 treatment was very well tolerated. In fact, it was much better tolerated than expected and far better tolerated than reported in the previous trial using methylphenidate alone. “We believe this may be due to the nutrient supplement’s protective effect on the mitochondria, specifically within the nervous and endocrine systems.”Dr. Kaiser

Central nervous system stimulants like methylphenidate are powerful drugs that can have significant side effects. Dr. Kaiser said considerable concern was expressed regarding the effects of a stimulant on a possibly already stressed nervous system, but the drug combination proved safe. Methylphenidate appeared to be safe in the 2006 trial as well, but significantly fewer side effects occurred in the Synergy trial.

Kaiser’s thesis – that the nutrients would add both protection and enhance the response to methylphenidate – appeared to be accurate.

The Next Trial (The Next Trial?)

The next trial, if it occurs will be much, much bigger and more expensive.

Will the K Pax formula become the first FDA approved treatment for ME/CFS? The next trial, if it occurs will be much, much bigger and more expensive.

I asked Dr. Kaiser if he was satisfied with the response rate.  He sounded like he was moderately satisfied but felt like they could do better, and listed four ways in which he expected that the next trial, if it is done, would have better results.

  1. Employing a crossover trial in which the patient goes from placebo to drug or drug to placebo should help reduce the placebo issue that occurred in this trial.
  2. When used in conjunction with the nutrients methylphenidate was found to be safe at all doses.  That suggested a higher and possibly more effective dose would be tolerated.
  3. The declining benefits of the placebo treatment and the increasing benefits of the Synergy formula over time, suggested a longer trial would have produced better statistical results.
  4. The addition of ubiquinol (C0Q10) (100mg/day) to the formula should add an extra punch.

The Synergy group is trawling through 2,000 pages of data. We’ll get more results on what percentage of patients had a clinically significant result later.

Wrap Up

All in all it was an odd result. A trial that succeeded on several levels but not on an important one. A trial that appeared, to be honest, to run into a bit of bad luck.

Dr. Kaiser said he was encouraged by the safety and efficacy data but whether the Synergy team will be able to move on and possibly produce the first FDA approved treatment for ME/CFS is unclear. Because no drugs have been approved for ME/CFS, one Phase III trial might be all the CDC requires. The results of this trial, however, suggest the next one will have to be much larger and more expensive to meet the FDA’s requirements.

The Synergy team doesn’t have deep pockets. They’re looking for partners – individuals, pharmaceutical companies – and grants to raise the money for another trial.

Have you tried the Synergy formula or K Pax’s Fatigue and Energy Pack that uses caffeine instead of Ritalin? Tell us how it went here:

John Kaiser on the Synergy Trial

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