Should I read a protocol?

Stimulated by Huang et al 2020.[1]

Image by Kai Dahms on Unsplash.

This is the first BMAS blog that highlights a protocol, rather than the results of research. I rarely read protocols! If it looks like a big study or I know the team, I might have a quick look at the abstract. Protocols really come in handy when performing peer review of the resulting research paper. The protocol allows you to check that the methods have not been changed in any way from what had been originally planned. It is always a good sign if the methods of a paper exactly match those in the protocol, but sometimes it is inevitable that there needs to be some alteration.

Anyway, there are no answers in protocols for the clinician, so if you are not a peer reviewer, why bother?

This one caught my eye because the fourth of the 22 authors is our friend Lisa, who runs the Women’s Health Day for the BMAS each year – it is coming up soon too (29th April 2020).

The other 21 authors are all Chinese, and I am starting to recognise one or two of these names as well.

PCOS – polycystic ovarian syndrome

This will be another huge trial of acupuncture and electroacupuncture (EA) in PCOS (polycystic ovarian syndrome). They are planning to recruit 1100 women. If they succeed this will be one of the largest comparative RCTs ever performed. The Acupuncture in Routine Care (ARC) studies were big cohorts with a randomised component.[2] The three largest of these ran to n>3000, but they weren’t really comparative; acupuncture was either added to usual care or not added until after the primary outcome at 3 months.

I have discussed the first big sham-controlled trial of EA and clomiphene in PCOS on this blog previously here: Segmental EA falls short in ovulation induction. This was a four-arm, double-dummy comparative efficacy trial (n=1000), with a disappointing result for segmental EA, both in comparison to a non-segmental sham and to clomiphene.[3] Basically, clomiphene was twice as good, and EA was no better than sham in terms of live birth rate.

In the proposed trial, sham EA has been dropped, and instead we have two ‘active’ acupuncture arms: personalised acupuncture and Lisa’s segmental EA protocol. Instead of clomiphene we now have letrozole, which has proven to be somewhat better than clomiphene.[4] The fourth arm will be placebo letrozole, making this a four-arm comparative trial.

So, we have some important new comparisons here. EA proved only half as good as clomiphene previously, but the clomiphene group also had non-segmental sham EA, which involved superficial needling of pairs of non-acupuncture points on the upper arm bilaterally. This time we will have a head to head comparison of the acupuncture groups with both the letrozole and the placebo pill equivalent. I am under no illusions that acupuncture can compete with such a powerful pharmacological intervention as you get by blocking aromatase (CYP19A1 or oestrogen synthase); however, it will be interesting to see where acupuncture sits between the active and dummy drug without those groups having the added context of sham acupuncture to help them along.

segmental EA is likely to have a stronger physiological effect

The most fascinating aspect of this protocol for me is the fact that individualised acupuncture is pitted against a segmental EA protocol that has proven effective in numerous laboratory and clinical studies in PCOS.[5] Individualised acupuncture here is the best TCM-based individualised approach. So essentially this is a test of TCM theory, since the physiological effect of the needling is unlikely to differ much. If anything, the segmental EA is likely to have a stronger physiological effect.

Having said that, the outcome here is LBR – live birth rate, which is a long way down the line from the physiology of ovulation induction.

This is a very risky move for TCM, and I would certainly not have advised this approach. The likely result is that there will be no significant difference between the acupuncture groups. Where will that leave TCM theory?

If there is a significant benefit of the individualised approach, without any plausible mechanisms to explain the difference, it will raise questions concerning the introduction of bias. As far as I can see, there is nothing to gain and a lot to lose.


1         Huang S, Hu M, Ng EHY, et al. A multicenter randomized trial of personalized acupuncture, fixed acupuncture, letrozole, and placebo letrozole on live birth in infertile women with polycystic ovary syndrome. Trials 2020;21:239. doi:10.1186/s13063-020-4154-1

2         Cummings M. Modellvorhaben Akupunktur–a summary of the ART, ARC and GERAC trials. Acupunct Med 2009;27:26–30. doi:10.1136/aim.2008.000281

3         Wu X-K, Stener-Victorin E, Kuang H-Y, et al. Effect of Acupuncture and Clomiphene in Chinese Women With Polycystic Ovary Syndrome: A Randomized Clinical Trial. JAMA 2017;317:2502–14. doi:10.1001/jama.2017.7217

4         Legro RS, Zhang H, Eunice Kennedy Shriver NICHD Reproductive Medicine Network. Letrozole or Clomiphene for Infertility in the Polycystic Ovary Syndrome. N Engl J Med 2014;371:1462–4. doi:10.1056/NEJMc1409550

5         Stener-Victorin E. Acupuncture in gynaecology and infertility. In: Filshie J, White A, Cummings M, eds. Medical Acupuncture – A Western Scientific Approach. London: Elsevier 2016. 536–51.

Declaration of interests MC