Randomized Trial Assessing Quinagolide Vaginal Ring for Endometriosis-related Pain

Study Overview
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Brief Summary
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To evaluate the efficacy of three doses of quinagolide administered as an extended-release vaginal ring compared to placebo on reduction of moderate to severe endometriosis-related pain

Official Title
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A Randomized, Double-blind, Placebo-controlled, Phase 2 Trial Assessing the Efficacy, Safety and Dose-response of Quinagolide Extended-release Vaginal Rings Administered Sequentially for 4 Menstrual Cycles in Women With Moderate to Severe Endometriosis-related Pain

Conditions
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Endometriosis-related Pain

Intervention / Treatment
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* Drug: Quinagolide 360 µg
* Drug: Quinagolide 720 µg
* Drug: Quinagolide 1080 µg
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pre-menopausal females aged ≥18 years at time of signing informed consent(s) with regular menstrual cycles. Body mass index (BMI) of 18-42 kg/m2 (both inclusive) at screening. Initial confirmation of endometriosis by laparoscopy or laparotomy within the last 10 years before the run-in visit or visualization of persistent endometrioma by repeat ultrasound. Transvaginal ultrasound documenting a uterus with no clinically significant abnormalities and presence of at least one ovary with no clinically significant abnormalities (with the exception of endometrioma) at the run-in visit. Eligible participants experienced moderate to severe endometriosis-related pain, which was defined as at the run-in visit, the participant having an NRS score of ≥5 for the worst endometriosis related pain during the past menstrual cycle and at randomization, the participant having a mean daily NRS score of ≥4 for the worst endometriosis related pain during each run-in menstrual cycle. Exclusion Criteria: History of no relief of endometriosis related pain after any medical therapy or surgery. However, history of partial pain relief, discontinuation due to side effects are not exclusionary. Known bone diseases (e.g. osteoporosis, Paget's disease and osteomalacia) affecting bone resorption or bone formation markers. Any significant abnormal findings of heart examinations before randomization. History of mental illness including occurrence of acute psychosis, bipolar disorders and schizophrenia (except for well-controlled anxiety and/or depression with no changes to interventions for 6 months prior to start of run-in) History of impulse control disorders including pathological gambling, compulsive buying, hypersexuality, and binge eating or being identified with potential impulse control disorder by the questionnaire for impulsive-compulsive disorders (a score ≥2 for any sub-questions of Question 3 or a score ≥1 for any sub-questions of Question 4) prior to randomization. History of orthostatic hypotension or recurrent syncope.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Quinagolide 360 µg<br>Vaginal ring containing Quinagolide 360 μg, with daily target release rate of 4.5 μg | Drug: Quinagolide 360 µg<br>* Vaginal ring containing quinagolide 360 µg for daily releases<br>* Other names: FE 999051;|
| Experimental: Quinagolide 720 µg<br>Vaginal ring containing Quinagolide 720 μg, with daily target release rate of 9 μg | Drug: Quinagolide 720 µg<br>* Vaginal ring containing quinagolide 720 µg for daily releases<br>* Other names: FE 999051;|
| Experimental: Quinagolide 1080 µg<br>Vaginal ring containing Quinagolide 1080 μg, with daily target release rate of 13.5 μg | Drug: Quinagolide 1080 µg<br>* Vaginal ring containing quinagolide 1080 µg for daily releases<br>* Other names: FE 999051;|
| Placebo Comparator: Placebo<br>Vaginal ring containing matching placebo | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Endometriosis-related Pain. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes from baseline to cycle 4. | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Endometriosis-related Pain on Days With Menstrual Bleeding and for the Worst Endometriosis-related Pain on Days With no Menstrual Bleeding | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Days with menstrual bleeding (dysmenorrhea). No menstrual bleeding (non-menstrual pelvic pain) Changes from baseline to cycle 4 | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Endometriosis-related Pain. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes over 4 menstrual cycles | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Dysmenorrhea. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes over 4 menstrual cycles | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Non-menstrual Pelvic Pain. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes over 4 menstrual cycles | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Dyspareunia on Days With Sexual Intercourse. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes over 4 menstrual cycles. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Frequency of Avoiding Sexual Intercourse Due to Expected Pain | The participants recorded daily if they had sexual intercourse, in an e-diary. For the days when participants did not have intercourse, the participant recorded if the reason for not having intercourse was because they expected pain: Yes (I did not have intercourse this day, because I expected pain) or No (I did not have intercourse this day, but this was not because I expected pain). The numbers represent the cumulative number of days with no intercourse, summed across all participants. In some cases, there are missing data as not every participant completed the e-diary for 100% of study days. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Daily Numerical Rating Scale (NRS) Scores for the Worst Impact of Endometriosis-related Pain on the Subject's Ability to Function. | Assessed daily by participants in an e-Diary. NRS is an 11-point scale, with 0 indicating no pain and 10 indicating the worst imaginable pain. Changes over 4 menstrual cycles. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Weekly Scores of the Endometriosis Health Profile-30 (EHP-30) Pain Impact Domain. | Assessed weekly by participants in an e-Diary. EHP-30 is a quality-of-life questionnaire. Score ranges from 0-100 and lower score denotes improvement. Changes over 4 menstrual cycles. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in Vaginal Bleeding Pattern - Number of Days With Bleeding Related to Period | The participants recorded daily if they had any vaginal bleeding during the past 24 hours, in an e-diary. Of the participants who had a bleeding, the participant recorded if this was menstrual bleeding: Yes (I had a vaginal bleeding that was menstrual bleeding) or No (I had a vaginal bleeding that was not menstrual bleeding). The numbers represent the cumulative number of days with vaginal bleeding, summed across all participants. In some cases, there are missing data as not every participant completed the e-diary for 100% of study days. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in Vaginal Bleeding Pattern. | The participants recorded daily if they had any vaginal bleeding during the past 24 hours, in an e-diary. Of the participants who had a bleeding, the participant recorded the assessed bleeding volume as either spotting (tiny amount of blood on underwear or panty liners), light bleeding (requiring 1-3 sanitary pads or tampons per day), moderate bleeding (requiring 4-6 sanitary pads or tampons per day), or heavy bleeding (requiring more than 6 sanitary pads or tampons per day). The numbers represent the cumulative number of days with vaginal bleeding, summed across all participants. In some cases, there are missing data as not every participant completed the e-diary for 100% of study days. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Percentage of Days With Mild and/or Strong Rescue Analgesics Used | Assessed daily by participants in an e-Diary | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Total and Average Doses of Mild and/or Strong Rescue Analgesics Used | Assessed daily by participants in an e-Diary | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Responder Rate | Assessed as ≥30%, ≥50% and ≥70% reduction from the baseline in mean daily NRS score for the worst endometriosis-related pain, dysmenorrhea and non-menstrual pelvic pain and for the worst endometriosis-related pain impact | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Mean Individual and Total Symptom and Sign Severity Scores | Assessed by the Biberoglu and Behrman (B&B) scale which is a 4-point scale with 0=none and 3=severe. The scores are the mean individual scores. The B&B scale consists of two parts. The first part of the B&B scale evaluates symptoms of endometriosis (i.e. pain). There are 3 subscales: pelvic pain(A, 0=none and 3=severe), dysmenorrhea (B, 0=none and 3=severe), and dyspareunia(C, 0=none and 3=severe). The total pelvic pain score is the sum of the three scores, i.e. A+B+C, which can range from 0 to 9. The second part of the B&B scale evaluates signs of endometriosis. There are 2 subscales pelvic tenderness (D, 0=none and 3=severe) and induration (E, 0=none and 3=severe) based on findings from a pelvic examination. The total physical pain score is the sum of the two scores, i.e. D+E, which can range from 0 to 6. The total symptom and sign severity score is the sum of all five scores, i.e. A+B+C+D+E, which can range from 0 to 15. The values are the change from baseline to cycle 4. | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in the Endometriosis Health Profile-30 (EHP-30) Scores | Assessed by the EHP-30 quality-of-life questionnaire completed by participants. Score ranges from 0-100 with lower score denoting improvement. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in Patient Global Impression of Severity (PGIS) Scores | Assessed by the PGIS scale completed by participants. PGIS is a 6-point scale depicting a participant's rating of their current conditions from good to bad. It ranges from 0 (none) to 5 (very severe). | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Patient Global Impression of Change (PGIC) Scores | Assessed by the PGIC scale completed by participants. PGIC is a 7-point scale depicting a patient's rating of their overall improvement from good to bad. | At cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Plasma Concentration of Quinagolide and Metabolites | Assessed by blood samples collection | Within 5 days after first ring insertion and at around 1 month, 3 months, 3.5 months and 4 months after baseline (each cycle is approximately 28 days) | 
| Serum Levels of Mid-luteal Phase Progesterone | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Number of Subjects With Serum Mid-luteal Progesterone Levels ≥25 Nmol/L (7.9 ng/ml) | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Serum Levels of Estradiol | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Serum Levels of Prolactin | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Serum Levels of Thyrotropin (TSH) | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Serum Levels of Insulin-like Growth Factor-1 (IGF-1) | Assessed by blood samples collection | At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days) | 
| Changes in Bone Turnover Markers, Determined by Bone Resorption Marker Serum C-terminal Crosslinking Telopeptide of Type 1 Collagen (s-CTx) | Assessed by blood samples collection. Changes from baseline to cycle 4 | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in Bone Turnover Markers, Determined by Bone Formation Marker Serum Procollagen Type I N Propeptide (s-PINP) | Assessed by blood samples collection. Changes from baseline to cycle 4 | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in ECG Parameters Including PR Interval at Cycle 4 | Assessed by 12-lead ECG | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in ECG Parameters Including QRS Duration at Cycle 4 | Assessed by 12-lead ECG | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in ECG Parameters Including QT Interval at Cycle 4 | Assessed by 12-lead ECG | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Changes in ECG Parameters Including QTcF Interval at Cycle 4 | Assessed by 12-lead ECG | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Proportion of Subjects With Abnormal Clinically Significant Echocardiography Findings Indicating Valvular Heart Disease | Assessed by echocardiography. Each echocardiography was to be assessed as normal or abnormal according to American College of Cardiology/American Heart Association guidelines for valvular heart disease. If abnormal, the level of valvular regurgitation and valvular stenosis was specified as mild, moderate or severe and valvular structure was evaluated as well. Measured at cycle 4. | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Proportion of Subjects Identified With Potential Impulse Control Disorders | Assessed by the questionnaire for impulsive-compulsive disorders completed by participants. Measured at cycle 4. | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Frequency and Intensity of Adverse Events | Assessed by an Adverse Events Log completed by the Investigator | From signing informed consent through study completion, around 8 months | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Albumin | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Alkaline Phosphatase | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Alanine Aminotransferase | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Aspartate Aminotransferase | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Bicarbonate | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Direct Bilirubin | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Bilirubin | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Calcium | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Cholesterol | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Chloride | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Creatinine | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Gamma Glutamyl Transferase | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Glucose | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Potassium | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Lactate Dehydrogenase | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Phosphate | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Protein | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Sodium | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Urate | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Chemistry Parameters: Urea Nitrogen | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Basophils Absolute | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Basophils | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Eosinophils Absolute | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Eosinophils | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Hematocrit | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Hemoglobin | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Lymphocytes Absolute | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Lymphocytes | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Ery. Mean Corpuscular Hemoglobin | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Ery. Mean Corpuscular HGB Concentration | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Ery. Mean Corpuscular Volume | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Monocytes Absolute | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Monocytes | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Neutrophils Absolute | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Neutrophils | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Platelets | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Erythrocytes | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Changes in Circulating Levels of Clinical Haematology Parameters: Leukocytes | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Urinalysis Parameters (Protein, Glucose, Bilirubin, pH, Nitrite, Ketone, Urobilinogen, Blood, Leukocytes, and Specific Gravity) | Assessed by urine sample collection (dip-stick test). Overall Urinalysis Result. | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Proportion of Subjects With Markedly Abnormal Changes in Circulating Levels of Clinical Chemistry Parameters | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Proportion of Subjects With Markedly Abnormal Changes in Circulating Levels of Clinical Haematology Parameters | Assessed by blood samples collection | At baseline and at menstrual cycle 4 (around 4 months) | 
| Proportion of Subjects With Markedly Abnormal Changes in Urinalysis Parameters | Assessed by urine samples collection | At baseline and at menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Frequency and Intensity of Ring Acceptability Parameters: Insertion of the Vaginal Ring | Assessed by a questionnaire completed by participants, addressing ring insertion | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Frequency and Intensity of Ring Acceptability Parameters: Removal of the Vaginal Ring | Assessed by a questionnaire completed by participants, addressing ring removal. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) | 
| Frequency and Intensity of Ring Acceptability Parameters: Felt the Ring | Assessed by a questionnaire completed by participants, addressing any feeling of the ring while the ring is in the body. | From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days) |