The mechanism of uterine fibroids is currently unclear, but many studies have revealed that it is a hormone dependent tumor whose growth is closely related to estrogen and progesterone. About 30% of patients may experience symptoms such as irregular bleeding, dysmenorrhea, and uterine fibroids affecting the uterus, leading to infertility At present, surgical treatment is the main treatment for uterine fibroids, but the postoperative recurrence rate is high and there is a lack of products that can control its progression in the long term. Ulipristal Acetate powder is a selective progesterone receptor modulator developed by HRA Pharmaceuticals. It was approved for marketing by the US Food and Drug Administration (FDA) in August 2010 under the trade name Ella. Used for the prevention of pregnancy within 120 hours after unprotected sexual activity or known or suspected contraceptive failure.
Can Ulipristal control uterine fibroids?
The latest research has found that as a selective progesterone receptor modulator, Ulipristal acetate (referred to as UPA in this article) can significantly reduce the volume of fibroids, control bleeding symptoms, and can be used preoperatively to reduce surgical difficulty. For patients who currently have fertility requirements, intermittent use of UPA may reduce fibroids to a size that does not require surgical treatment, bringing hope for fertility to patients. For patients with multiple fibroids during perimenopause, intermittent use of UPA until menopause may prevent them from undergoing hysterectomy.
Review of Clinical Trials of CDB-2914
| Selective progesterone receptor modulator |
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| Selectively inhibit Pg, but not E2. | |
| PEARL I: | Compared with placebo, preoperative application of UPA 13w significantly reduced uterine fibroid-related bleeding and reduced tumor volume. |
| PEARL II: | 5 mg/d or 10mg/d UPA 3m is not inferior to leuprorelin acetate in controlling bleeding. |
| PEARL III: | Long-term application of UPA (UPA 10 mg 3m) *4 cycle can effectively control uterine fibroid-related bleeding and reduce tumor volume, without causing endometrial lesions, with high safety. |
| Pearl IV: | Long-term application of 5 mg/d and 10mg/d (intermittent 12w+10-18d) can control the symptoms of menorrhagia well. Although the single cycle effect of 10 mg/d is better, the amenorrhea rate of 5mg/d has reached 80% in two weeks, which can meet the clinical needs. |
New observational experiments in UK
| Multi center, prospective, observational clinical studies |
| Inclusion of patients: premenopausal women with symptomatic uterine fibroids, surgical indications, and preoperative use of UPA |
| Research location: 73 clinical centers in Europe (Germany, France, England, Portugal, Romania, Sweden, Poland, Hungary, Slovenia, Australia) |
| Research period: May.24,2014-Apr.16, 2012 |
Medication and follow-up plan
| UPA 5mg/d for no more than 3 months (approved by the European Medicines Agency) |
| Follow up will be conducted every 3, 6, 9, 12, and 15 months after enrollment to record changes in UPA dosage, symptoms of uterine fibroids, subsequent surgical/treatment status, severe/general adverse reactions, etc, |
| According to the Clinical Global Impression Improvement scoring system, a symptom improvement score is given (1 point for significant improvement -7 points for significant deterioration) |
| Using the Patient Treatment Benefit Scale (PTBS) to score the degree of improvement in patients' own symptoms, patients rated themselves based on their feelings over the past 3 months, with 1-significant improvement; 2- Improvement; 3- No difference; 4- Deterioration |
| UFS QoL Symptom Severity Score Evaluation of Patient Symptom Severity |
| During the follow-up process, if various endometrial changes (simple/complex hyperplasia, malignant transformation, etc.) occur, pathological sections must be obtained and handed over to pathologists for evaluation |
Patient follow-up intention
| Table 1 | |
| Patient Disposition. | Analysis Set Study Population |
| Number of Patients at Baseline | 1473 |
| Visit 1 (at Month 3) | 1262 |
| Visit 2 (at Month 6) | 1020 |
| Visit 3 (at Month 9) | 806 |
| Visit 4 (at Month 12) | 735 |
| Visit 5 (at Month 15) | 636 |
| End of Study Visit | 1473 |
| Unscheduled Visit | 488 |
| ª Patient discontinuing during the study were asked to complete an end of study visit | |
| The average age is 42 years old, with 40-50 years old accounting for 58% and 30-40 years old accounting for 25% | |
UPA follow-up treatment
| 571 (38.8%) patients underwent subsequent surgical treatment with an average interval of 11 weeks, among ♦ Digging fibroids 277 (48.5%) ◆ Uterine resection 227 (39.8%) Vascular embolism 23 (4%) Endometrial damage 14 (2.5%) High intensity focused ultrasound 2 (0.4%) ◆ Other 28 (4.9%) |
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Patient symptom improvement
| After 3 months of medication, 65.7% of patients believed that their symptoms had "significantly improved" The Clinical Global Impression Improvement score showed that at the 3-month follow-up, 60.1% of patients had "significant or relatively improved" clinical symptoms, followed by 47.9% at the subsequent 4 follow-up visits, 48.5%, 48.4%, 51.2% The UFS QoL symptom severity score has decreased from an initial average of 25 points to an average of 15 points |
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Security
331 (22.5%) people experienced adverse reactions, with a total of 691 adverse events, and 523 adverse events occurred during UPA treatment. Among the adverse reactions that occurred during the non treatment period, 359 AEs were also considered to be related to UPA treatment.
At the 3-month follow-up, the incidence of endometrial thickening was 8.9%, and 2.8% of patients had a thickness greater than 1.6cm
Thirty patients underwent endometrial biopsy, and a total of 33 specimens were sent. 14 (1.0%) cases of selective progesterone receptor modulators associated endometrial changes (PAEC) were found, with 9 (0.6%) cases of simple endometrial hyperplasia, 2 (0.1%) cases of atypical hyperplasia, and 2 (0.1%) cases of endometrial adenocarcinoma.
After final pathological review, 2 cases of atypical hyperplasia were diagnosed as PAECs, while only 5 cases were confirmed as PAECs in the original PAECs. Many other specimens have not been rechecked, resulting in a lack of clear diagnosis.
progesterone receptor modulators associated endometrial changes (PAEC)
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Selective progesterone receptor modulators associated with endometrial changes UPA can induce a series of morphological changes in the endometrium, including changes in large cystic glands and stromal components (fibroblasts and blood vessels), known as Progesterone Receptor Modulator Associated Endometrial Changes (PAEC). |
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Serious adverse reactions
1: Among them, 77 adverse reactions were considered as "serious adverse events (SAEs)", occurring in 57 patients and 34 during UPA treatment.
2: In SAE, there were 2 cases of endometrial cancer, 2 cases of uterine sarcoma, and 1 case of leiomyosarcoma. The leiomyosarcoma researchers believed that it was related to UPA treatment: the patient was 55 years old, G1P1, and had no improvement in uterine fibroid symptoms or reduction in fibroid volume after 3 months of UPA treatment. Two and a half months after the end of treatment, a hysterectomy was performed, and pathological examination showed leiomyosarcoma. Afterwards, receive follow-up treatment.
3: Fibrosarcoma is rare in the uterus and has a low possibility of confusion with uterine fibroids at the time of inclusion. Therefore, researchers believe that the malignancy in this case may be related to UPA treatment
Discuss
1: UPA can be safely applied to uterine fibroids
2: All patients had surgical indications at the time of enrollment. After 3 months of UPA, only 38.8% of patients underwent surgery, indicating that the use of UPA can prolong or delay the surgery time, and even some patients avoid surgical treatment
3: PAEC may occur, but it can be completely reversed after stopping UPA treatment. Patients should undergo endometrial biopsy before initial UPA treatment to rule out endometrial cancer.
4: After discontinuing the medication, the patient's adverse reactions significantly decreased, but the UFS QoL symptom severity score continued to decline, indicating that UPA has a significant delaying effect and can control uterine fibroids during a period of discontinuation
Advantages and disadvantages
advantage
Large sample observational study, the first batch of studies that began immediately after the approval of UPA for uterine fibroids in Europe in 2012
Proposed unique application prospects
Insufficient
Observational studies without controls are not convincing
Incomplete data, missing information on symptoms, adverse reactions, etc
Outlook and Prospect
UPA has good prospects for clinical application. Currently, there is a lack of oral drugs that can control uterine fibroids in the long term, except for GnRH-a. The emergence of UPA fills this gap
♦ Sustainable intermittent medication (UPA3m+intermittent 10-18d), lasting for 1 year or more
♦ Suitable for special populations:
♦ 1. For perimenopausal patients, oral medication should be taken to avoid surgical treatment;
♦ 2. Patients with fertility requirements can conceive in the short term after controlling their symptoms;
Disadvantages: expensive price, frequent adverse reactions
UPA has been approved in Europe to treat symptomatic uterine fibroids with 5mg/d or to reduce fibroid volume before surgery, but the single use should not exceed 3 months. After the PEARL trial, the US FDA is expected to approve its application.
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