SPIRIT 1 (&2)… Relugolix endometriosis therapy

Endometriosis is a common disease that effects 10 % of women of reproductive age leading to chronic pelvic pain, infertility and significant loss of function. Endometriosis is probably under-diagnosed particularly in lower income countries where access to laparoscopic surgery and advanced imaging is limited. Even once appropriately diagnosed the treatment of endometriosis is complicated and often not curative leaving many women with chronic pain, infertility and requiring repeat surgeries to improve outcomes. The nature of the symptoms means that many women also suffer from a significant mental health burden as part of this syndrome. In short, this is a disease that requires renewed attention and research to improve outcomes for so many women.

For the last 15 years I have worked as a Anaesthetist doing work mainly in gynaecological surgery. I have seen the suffering and pain that this disease can cause and the frustration that many women feel with our modern interventions which are often incompletely efficacious and come with significant side effects.

The mainstay of treatment for endometriosis involves:

1. Surgery – this is both diagnostic and allows for the removal of symptomatic ectopic endometrial tissue with the goal of decreasing inflammation, pain and improving fertility.
2. Hormonal treatment – the use of various contraceptive agents to suppress menstruation can limit endometrial proliferation. However, these all come with side effects and obviously limit fertility.
3. Analgesia – using anti-inflammatories and other analgesics is part of symptomatic care. These are al limited in effect and come with side effects too. The incidence of chronic pain in women with endometriosis is high and presents a challenge for patients and clinicians trying to alleviate suffering.
4. Gonadotrophin-releasing hormone analogues have been used to suppress the pituitary axis and therefore remove the stimulation of endometrial tissue. Whilst effective in reducing symptoms, GnRH analogues are limited by the risk of inducing menopausal symptoms and associated osteoporosis risk.

This is where the SPIRIT trial(s) come into play. [DOWNLOAD A COPY HERE] The SPIRIT trial studies the use of a combination of GnRH-analogue in addition to low dose combined oestrogen/progesterone in order to maintain baseline hormone levels whilst suppressing the cyclical stimulation of endometrial deposits.

So let’s take a look at this trial (actually two trials) to understand what this means for women with endometriosis in 2022. Why two trials? That is a good question! The authors state that they were required to run 2 separate trials in order to satisfy the regulatory requirements in order to be able to license and market this medication…. so essentially they ran two identical trials simultaneously. There was a small overlap geographically in some of the 219 site locations. Interestingly the sample size calculation for each trial was to have 200 women in each arm – so 600 randomised. Which they did achieve… but.. one does wonder if it would have been better to just run it as one big trial? After the inevitable loss to follow up neither trial had enough women to meet this sample calculation, but added together they were well past the recruitment required!

We will start with an RCT EBM checklist:

Population:   Women aged 18 – 50 years (premenopausal) with surgically diagnosed / directly-visualised endometriosis within the previous 10 years. The participants were required to have moderate or severe symptoms in the month leading into randomisation as scored by some common rating scores. These women were recruited from 219 community and hospital research centres in Africa, Australasia, Europe, North America, and South America. There were 638 women randomised in SPRIT 1 and 623 in SPIRIT 2 – a total of 1261 in total.

Women underwent a month of “run in” placebo therapy in order to identify “strong placebo responders” and not include them in the trial – this is unusual in trials of therapies like this. In theory, this should make the results more robust as the probability of response is likely to be smaller once this group are removed from the trial. Ergo, any response detected is less likely to be placebo…

Intervention: This was a triple armed, randomised, doule-blinded RCT. Women were allocated to one of 3 groups in a 1:1:1 ratio. There were 2 different interventions in this trial – the researchers trialed 2 different protocols – one with regulolix as monotherapy then in combination, the other was continuous combination therapy with oestrogen / progesterone.

1. Continuous regulolix combination therapy: once-daily relugolix 40 mg orally as a tablet in combination with daily estradiol 1 mg and norethisterone acetate 0·5 mg orally as a capsule for 24 weeks.
2. Delayed relugolix combination therapy: (relugolix 40 mg monotherapy for 12 weeks followed by relugolix combination therapy each for 12 weeks. The researchers included this group as they wanted to measure the potential menopausal effect of monotherapy.

Comparison: Placebo tablets identical to trial medications and analgesics as required. This was a well-blinded trial in terms of the packaging and pill presentation.

Outcome:     The primary outcome was the proportion of “responders” – this was defined by the application of a Numerical Rating Scale (1 – 10) score (actually 2 NRS scores – one for dysmenorrhea and one for non-menstrual pain). So you can see it starts to get a little tricky as we actually have 2 scores being counted as a primary outcome…

The definition of “responder” was complicated. With the actual trial data being used (in a blinded analysis) to come up with what the authors call a “meaningful change threshold” – basically how big an improvement in your various 1-10 scores was “meaningful”? After some statistical skullduggery they landed at 2.8 / 10 reduction of dysmenorrhea and 2.1/10 reduction of non-menstrual pain. IS this clinically “meaningful”? maybe…

Women who used an increased volume of analgesics were considered as “non-responders” for the analysis.

Women were given a smart phone with an app that allowed them to rate their symptoms daily on a variety of scales including the NRS for dysmenorrhea, non-menstrual pain, dyspareunia and a few other more global health metrics – this all gets quite confusing! The plan was to have real time recording of symptoms and analgesic usage in order to avoid recall bias which is a problem in trials with a 6 month follow-up period.

The primary outcome comparison was only considered in comparing the placebo group to the Continuous Combination group. The Delayed Regulolix group was compared as a secondary outome using the same rating scales.

Adverse events were followed and all women underwent bone densitometry in order to compare the effects of each group on on osteoporosis scores.

RESULTS: in graphical form here are the plots from each trial:

These bar charts do look impressive, and crucially the two SPIRIT trails are consistent with one another. If there had been a significant difference between the two trials despite the same design then this would have become a statistical and ethical headache for the researchers and the patients too. However, in my opinion we can probably just roll both trials into one lump as their design and conduct was identical..

Now the crux of the matter – a casual glance at the bar graphs above will tell you that there is a very big benefit to relugolix / hormones. I have crunched the numbers and taken as a single trial there is approximately a 45% increase in response for dysmenorrhea and a 21% increase for non-menstrual pain… those are impressive numbers – it gets you an NNT of 2 – 5! However, what does that really mean in terms of absolute reduction in symptom scores?

The “responder” rate is really just an arbitrary line in the sand. What women really care about is the reduction in symptoms. If you look at the raw NRS scores then you see that the improvement in symptoms was about 3/10 for dysmenorrhea and 1/10 for non-menstrual pain. Only one of these meets the criteria set out in the trial as being a “meaningful change” by their own definition.

The authors also reported a difference in the secondary outcome of opioid analgesic use. This is merely a secondary outcome and possibly would make a more objective measure of pain improvement [it is a messy outcome either way] … however in both SPIRITS they found a 9% and 16% increase in the number of women who did not require opiates

In terms of adverse effects – there were no major differences with the exception that there was a significant loss of bone density in the monotherapy groups (ie. those with 12 weeks of exposure to relugolix with no oestrogen in addition). They report a significant increase in vasomotor symptoms in women in the monotherapy phase of the delayed groups. Annoyingly, this data is not really presented in the paper and no confidence intervals or p-values are calculated…. so we just have to trust the authors here! Either way it seems that the use of monotherpay without the hormone combination is overall not so great for a few reasons – osteoporosis and inducing menopausal symptoms.

Authors’ Conclusions:

“Once-daily relugolix combination therapy significantly improved endometriosis-associated pain and
was well tolerated. This oral therapy has the potential to address the unmet clinical need for long-term medical treatment for endometriosis, reducing the need for opioid use or repeated surgical treatment.”

Quality Checklist:

1. The patients were adequately randomized.   YES

2. The randomization process was concealed.  YES

3. The patients were analyzed in the groups to which they were randomized.  YES

4. The study patients were recruited consecutively (i.e. no selection bias). NOT CLEAR

5. The patients in both groups were similar with respect to prognostic factors.    YES

6. All participants (patients, clinicians, outcome assessors) were unaware of group allocation. 
– the patients were blinded throughout. The clinicians were not blinded for the initial run-in phase

7. All groups were treated equally except for the intervention.  YES

8. Follow-up was complete (i.e. at least 80% for both groups).  JUST over 80%

9. All patient-important outcomes were considered.  YES, I guess.
10. The treatment effect was large enough and precise enough to be clinically significant.   PRECISE but may be marginal in terms of “meaningful symptom reduction”

MY CONCLUSIONS

Overall I am excited to see this research being done. It is important that we continue to try and find safe and effective therapies for this disease. Endometriosis is common and the burden it places on young, otherwise healthy women is huge.

This will be regarded as a positive trial (s) and it looks like the goal of SPIRIT 1 & 2 will be achieved based on the numbers. I do not believe that it is a panacea – the effect size is more modest than the headline chart would have us believe. A small reduction in pain and maybe less analgesic use is how I would sell this.

It should be noted that only the combination or relugolix with oestrogen / norithisterone has been studied here. The use of monotherapy with relugolix is not a primary outcome and appears to have more adverse effects.

Also note that this is a 24 week trial of a chronic disease. We still do not know about the long term harms or benefits of this drug. There is an ongoing 80 week extension arm of this trial still ongoing… so as they say, watch this space.

So if I were a GP or Gynaecologist and a woman with moderate- severe endometriosis asked me about this drug I would say:

“Taking the combination formulation for up to 6 months may give you a modest improvement in dysmenorrhea and maybe less improvement for chronic background pain. We still don’t know what will happen when you stop taking this medication. However, if you are keen to try it then I think that would be reasonable for a period of time with a plan to assess your own response to this medication.”