Randomized Trial Assessing Quinagolide Vaginal Ring for Endometriosis-related Pain

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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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".

Time frame: At cycle 4 (around 4 months, each cycle is approximately 28 days)

Plasma Concentration of Quinagolide and Metabolites

Assessed by blood samples collection

Time frame: 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

Time frame: 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

Time frame: At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days)

Serum Levels of Estradiol

Assessed by blood samples collection

Time frame: At baseline and cycle 4 (around 3.5 months, each cycle is approximately 28 days)

Serum Levels of Prolactin

Assessed by blood samples collection

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: 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

Time frame: From signing informed consent through study completion, around 8 months

Changes in Circulating Levels of Clinical Chemistry Parameters: Albumin

Assessed by blood samples collection

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Bicarbonate

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Bilirubin

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Calcium

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Cholesterol

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Chloride

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Creatinine

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Glucose

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Potassium

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Phosphate

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Protein

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Sodium

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Chemistry Parameters: Urate

Assessed by blood samples collection

Time frame: 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

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Basophils

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Eosinophils

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Hematocrit

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Hemoglobin

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Lymphocytes

Assessed by blood samples collection

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Monocytes

Assessed by blood samples collection

Time frame: 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

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Neutrophils

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Platelets

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Erythrocytes

Assessed by blood samples collection

Time frame: At baseline and at menstrual cycle 4 (around 4 months)

Changes in Circulating Levels of Clinical Haematology Parameters: Leukocytes

Assessed by blood samples collection

Time frame: 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.

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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

Time frame: 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.

Time frame: 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.

Time frame: From baseline to menstrual cycle 4 (around 4 months, each cycle is approximately 28 days)