Primary Dysmenorrhea
Conditions
Brief summary
The purpose of this study is to further assess the efficacy, safety and dose-response of KYG0395 in the treatment of primary dysmenorrhea.
Detailed description
Compare the effect and safety of the investigational drug and placebo on dysmenorrhea in adult otherwise healthy women.
Interventions
DRUGhigh dose KYG0395
3 KYG0395 capsules tid (morning, midday, and evening)
DRUGlower dose KYG0395
3 KYG0395 capsules 2 times a day (bid) (morning and evening) plus 3 capsules of placebo (midday)
DRUGPlacebo
3 capsules of placebo tid (morning, midday, and evening)
Sponsors
Jiangsu Kanion Pharmaceutical Co., Ltd
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 35 Years
Healthy volunteers
No
Inclusion criteria
1. Reviewed and signed the ICF. 2. Female between the ages of 18 and 35 (inclusive) at the time of signing the ICF. 3. Otherwise healthy female subjects with primary dysmenorrhea for at least 3 consecutive menstrual cycles prior to the study (prior to the start of the baseline cycles) and with VAS score \>70 for the maximum dysmenorrheic pain or VAS score \>40 for the average daily dysmenorrheic pain of the last menstrual cycle. 4. Recent (last 6 months) history of regular menstrual cycles. Regular menstrual cycle meant the period of the cycle fell in the range of 21 to 35 days. 5. No contraceptive injection, implant, or intrauterine device within 6 months prior to the study and willing not to use any of them during the entire study period. Subject agreed to the use of a highly effective method of contraception throughout the study including: * 28-day regimens of combined oral contraceptives, patches, or rings * Bilateral tubal sterilization * Partner vasectomy * Condoms and spermicide * Diaphragm and spermicide At the discretion of the investigator, total abstinence was permitted as a method where age, lifestyle, or sexual orientation of the subject ensured compliance. If the subject was taking combined hormonal contraception, it had to be taken for at least 6 months prior to screening and be used throughout the duration of the study without interruption. No more than 50% of enrolled subjects were to be taking combined hormonal contraception. 6. Agreed not to use any dietary supplement or alternative medication intended to treat dysmenorrhea and/or its accompanying symptoms during the entire study period. 7. Was able to tolerate ibuprofen and willing to use only ibuprofen supplied by the sponsor for this study as a rescue medication. 8. Was able to understand and follow the study instructions, to complete the electronic subject diary, and to communicate with the investigator and staff.
Exclusion criteria
1. Known or suspected to have secondary dysmenorrhea due to pelvic inflammation, endometriosis, uterine myomata, ovarian pathological changes, or other pelvic diseases. 2. Known or suspected to have gastrointestinal or urological conditions that may cause abdominal/pelvic pain, such as colitis, appendicitis, irritable bowel syndrome, cholelithiasis, interstitial cystitis, urocystitis, nephrolithiasis, and other conditions that, according to the investigator's judgment, are not suitable for the study. 3. Use of an intrauterine contraceptive device, contraception injection, contraceptive implant, progesterone-only contraceptive pills, or an extended-cycle combined hormonal contraceptive regimen that does not foster cyclic withdrawal bleeding every 28 days within 6 months of screening or during the study. 4. Screening pelvic ultrasound findings suggestive of significant pathology including secondary causes of dysmenorrhea such as more than 2 uterine fibroids \>3 cm in diameter, or complex ovarian cysts. At the discretion of the investigator, simple ovarian cysts \<3 cm in diameter or functional ovarian cysts that were deemed to not require follow-up were permitted. 5. Obesity: body mass index (BMI) \>32 kg/m2. 6. Positive gonorrhea and/or chlamydia test or evidence of other active sexually transmitted disease that, in the investigator's opinion, would make the subject not suitable for the study. 7. Known allergy to the study drug, or hypersensitivity to any of the study drug ingredients, or known allergy or intolerance to one or more of the excipients: β cyclodextrin and lactose, and according to the investigator's judgment, the allergy/intolerance was so severe that the subject was not suitable for the study. 8. Presence of one or more than one of the following: cerebrovascular disease, cardiovascular disease, pulmonary embolism, coagulopathy, thrombophlebitis, optic neuritis, retinal vein thrombosis, liver tumor, kidney tumor, renal failure, hepatitis, or other serious primary diseases of hepatic, renal or hematopoietic systems and mental disorders that according to the investigator's judgment renders the subject unsuitable for the study; or any chronic disease(s) for which the subject had been taking long term medication, and according to the investigator's judgment was unsuitable for the study. The investigator may have contacted the medical monitor and/or sponsor with questions about whether a subject was suitable for the study. 9. Hypertension, defined as sitting blood pressure (BP) systolic \>140 mm Hg or diastolic \>90 mm Hg (repetition of the measurement of BP was permitted to confirm the subject's hypertension condition). 10. Pregnant or trying to conceive during the study. Recent delivery, abortion, or lactation within 3 menstrual cycles before the start of treatment. 11. Alcoholism or drug abuse within the last 6 months prior to the study. 12. Regular use of any concomitant medications that might have confounded efficacy and/or safety assessments including, but not limited to, the following: narcotic, non NSAID, or NSAID analgesics for the treatment of conditions other than dysmenorrhea, psychotropic drugs, antidepressants, sedative hypnotics, sedating antihistamines, muscle relaxants, or tranquilizers. Selective serotonin reuptake inhibitors and serotonin norepinephrine reuptake inhibitors were permitted for indications other than pain provided that the subject had been on a stable dose for at least 2 menstrual cycles before providing consent for this study and agreed to remain on a stable dose throughout the course of the study. 13. Simultaneous participation in another clinical study or use of any experimental drug or device, or being a subject in another clinical research program within 30 days prior to the screening visit. 14. Use of any dietary supplement or alternative medication intended to treat dysmenorrhea or its accompanying symptoms within 30 days prior to the screening visit. 15. Major surgery scheduled for the study period. 16. Known to have a positive human immunodeficiency virus test. 17. Abnormal Papanicolaou (PAP) test results, except atypical squamous cells of unknown significance with reflex human papillomavirus test negative. 18. Inability to follow study procedures for any reason, including the following examples: language comprehension, psychiatric illness, or inability to get to the study center. 19. Had a clinically significant deviation from normal in any of the screening tests or examinations. 20. Had the presence of all 3 of the following signs and symptoms during the 2 weeks prior to screening. * Reported that her usual urine color was grade 7 or above on the pictorial scale (provided in the GF-2011-001 Special Assessment Guide) and laboratory examination of the color of her urine at screening confirmed this * Reported that she usually had dry stools and had experienced constipation for at least 2 consecutive days * Was noted on the screening examination by the investigator to have a red tongue with a yellow coating (example photograph provided in the GF 2011 001 Special Assessment Guide)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Change From Baseline to the End of Treatment Period in Maximum Dysmenorrheic Pain VAS Score | Baseline and end of treatment (6 months) | VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up. |
| The Change From Baseline in Number of Days With Dysmenorrheic Pain at the End of Treatment | Baseline and end of treatment (6 months) | The change from baseline in number of days with dysmenorrheic pain at the end of 3 treatment cycles |
| The Change From Baseline to the End of Follow-up Period in the Maximum VAS Score | Baseline and end of follow-up (9 months) | VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up. |
| The Number of Days of Dysmenorrheic Pain at the End of Follow-up Period Compared With Baseline | Baseline and end of follow-up (9 months) | The change from baseline in the number of days with dysmenorrheic pain at the end of a 3-cycle follow-up period |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rescue Medication Consumption at the End of Treatment and Follow-up Period | Baseline, end of treatment (6 months) and end of follow-up (9 months) | The change from baseline to the end of treatment and follow-up period in rescue medication consumption |
| Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | Base line and end of follow-up (9 months) | The subject's evaluation of overall satisfaction was recorded in the electronic subject diary at the end of the 3 treatment cycles and at the end of the 3-cycle follow-up period (at the end of the day before the subject goes to bed) using the numeric rating scale provided below: 0=None, Not satisfied with the treatment outcome； 1. Mild, Mildly satisfied with the treatment outcome； 2. Most, Mostly satisfied with the treatment outcome； 3. Complete, Completely satisfied with the treatment outcome. |
| Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | Baseline, end of treatment (6 months) and end of follow-up (9 months) | VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| KYG0395 (High Dose Group) KYG0395: 3 KYG0395 capsules tid (morning, midday, and evening) | 81 |
| KYG0395 (Lower Dose Group) KYG0395: 3 KYG0395 capsules 2 times a day (bid) (morning and evening) plus 3 capsules of placebo (midday) | 77 |
| Placebo placebo: 3 capsules of placebo tid (morning, midday, and evening) | 80 |
| Total | 238 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 5 | 4 | 1 |
| Overall Study | Exclusion Criteria met during study | 2 | 1 | 0 |
| Overall Study | Lost to Follow-up | 8 | 13 | 6 |
| Overall Study | Physician Decision | 1 | 2 | 0 |
| Overall Study | Protocol Violation | 0 | 1 | 1 |
| Overall Study | sponsor decision | 1 | 6 | 2 |
| Overall Study | Withdrawal by Subject | 14 | 16 | 18 |
Baseline characteristics
| Characteristic | KYG0395 (High Dose Group) | KYG0395 (Lower Dose Group) | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 27.8 years STANDARD_DEVIATION 4.28 | 26.8 years STANDARD_DEVIATION 5.18 | 27.3 years STANDARD_DEVIATION 4.55 | 27.3 years STANDARD_DEVIATION 4.67 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 14 Participants | 11 Participants | 13 Participants | 38 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 67 Participants | 66 Participants | 67 Participants | 200 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Black or African American | 17 Participants | 19 Participants | 30 Participants | 66 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 3 Participants | 1 Participants | 7 Participants |
| Race (NIH/OMB) White | 59 Participants | 52 Participants | 46 Participants | 157 Participants |
| Sex: Female, Male Female | 81 Participants | 77 Participants | 80 Participants | 238 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 23 / 88 | 25 / 90 | 35 / 91 |
| serious Total, serious adverse events | 1 / 88 | 1 / 90 | 1 / 91 |
Outcome results
Primary
The Change From Baseline in Number of Days With Dysmenorrheic Pain at the End of Treatment
The change from baseline in number of days with dysmenorrheic pain at the end of 3 treatment cycles
Time frame: Baseline and end of treatment (6 months)
Population: Full analysis set: all randomized subjects who received at least 1 dose of study treatments, and had at least 1 valid postbaseline assessment of dysmenorrheic pain VAS score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KYG0395 (High Dose Group) | The Change From Baseline in Number of Days With Dysmenorrheic Pain at the End of Treatment | -1.4 days | Standard Error 0.17 |
| KYG0395 (Lower Dose Group) | The Change From Baseline in Number of Days With Dysmenorrheic Pain at the End of Treatment | -1.3 days | Standard Error 0.19 |
| Placebo | The Change From Baseline in Number of Days With Dysmenorrheic Pain at the End of Treatment | -1.1 days | Standard Error 0.18 |
Comparison: p value for multiple comparison among 3 arms and comparison between investigational drug and placebop-value: >0.05Mixed Models Analysis
Primary
The Change From Baseline to the End of Follow-up Period in the Maximum VAS Score
VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up.
Time frame: Baseline and end of follow-up (9 months)
Population: FAS: all randomized subjects who received at least 1 dose of study treatments, and had at least 1 valid postbaseline assessment of dysmenorrheic pain VAS score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KYG0395 (High Dose Group) | The Change From Baseline to the End of Follow-up Period in the Maximum VAS Score | -22.8 unit of a scale | Standard Error 2.93 |
| KYG0395 (Lower Dose Group) | The Change From Baseline to the End of Follow-up Period in the Maximum VAS Score | -15.5 unit of a scale | Standard Error 3.21 |
| Placebo | The Change From Baseline to the End of Follow-up Period in the Maximum VAS Score | -9.8 unit of a scale | Standard Error 2.79 |
p-value: <0.01Mixed Models Analysis
Primary
The Change From Baseline to the End of Treatment Period in Maximum Dysmenorrheic Pain VAS Score
VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up.
Time frame: Baseline and end of treatment (6 months)
Population: Full analysis set: all subjects who received at least one treatment dose and had one post-baseline assessment
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KYG0395 (High Dose Group) | The Change From Baseline to the End of Treatment Period in Maximum Dysmenorrheic Pain VAS Score | -19.8 units on a scale | Standard Error 2.84 |
| KYG0395 (Lower Dose Group) | The Change From Baseline to the End of Treatment Period in Maximum Dysmenorrheic Pain VAS Score | -18.0 units on a scale | Standard Error 3.07 |
| Placebo | The Change From Baseline to the End of Treatment Period in Maximum Dysmenorrheic Pain VAS Score | -14.4 units on a scale | Standard Error 2.86 |
p-value: >0.05Mixed Models Analysis
Primary
The Number of Days of Dysmenorrheic Pain at the End of Follow-up Period Compared With Baseline
The change from baseline in the number of days with dysmenorrheic pain at the end of a 3-cycle follow-up period
Time frame: Baseline and end of follow-up (9 months)
Population: FAS: all randomized subjects who received at least 1 dose of study treatments, and had at least 1 valid postbaseline assessment of dysmenorrheic pain VAS score
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| KYG0395 (High Dose Group) | The Number of Days of Dysmenorrheic Pain at the End of Follow-up Period Compared With Baseline | -1.3 days | Standard Error 0.19 |
| KYG0395 (Lower Dose Group) | The Number of Days of Dysmenorrheic Pain at the End of Follow-up Period Compared With Baseline | -1.5 days | Standard Error 0.21 |
| Placebo | The Number of Days of Dysmenorrheic Pain at the End of Follow-up Period Compared With Baseline | -1.0 days | Standard Error 0.18 |
p-value: <0.05Mixed Models Analysis
Secondary
Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period
VAS is represented by a straight line with extreme limits: from no pain and an associated image of a happy face at the left endpoint to unbearable pain and an associated image of an unhappy face at the right endpoint. The left endpoint is the minimum pain score of zero while the right endpoint is the maximum pain score of 100. The dysmenorrheic pain (lower abdominal cramping pain) that usually occurs just before and/or during menstruation was measured in this study using a The Visual Analogue Scale (VAS). Pain was assessed during 9 menstrual cycles from the beginning of the screening to the end of follow-up.
Time frame: Baseline, end of treatment (6 months) and end of follow-up (9 months)
Population: FAS: all randomized subjects who received at least 1 dose of study treatments, and had at least 1 valid postbaseline assessment of dysmenorrheic pain VAS score
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| KYG0395 (High Dose Group) | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of treatment | -14.7 pills | Standard Error 2.12 |
| KYG0395 (High Dose Group) | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of follow-up | -12.8 pills | Standard Error 2.15 |
| KYG0395 (Lower Dose Group) | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of treatment | -11.1 pills | Standard Error 2.29 |
| KYG0395 (Lower Dose Group) | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of follow-up | -10.1 pills | Standard Error 2.33 |
| Placebo | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of treatment | -9.6 pills | Standard Error 2.11 |
| Placebo | Average Daily Dysmenorrheic Pain VAS Score at the End of Treatment and Follow-up Period | at the end of follow-up | -9.1 pills | Standard Error 2.04 |
Secondary
Rescue Medication Consumption at the End of Treatment and Follow-up Period
The change from baseline to the end of treatment and follow-up period in rescue medication consumption
Time frame: Baseline, end of treatment (6 months) and end of follow-up (9 months)
Population: FAS: all randomized subjects who received at least 1 dose of study treatments, and had at least 1 valid postbaseline assessment of dysmenorrheic pain VAS score
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| KYG0395 (High Dose Group) | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of treatment | -2.6 pills | Standard Deviation 4.28 |
| KYG0395 (High Dose Group) | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of follow-up | -2.2 pills | Standard Deviation 4.66 |
| KYG0395 (Lower Dose Group) | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of treatment | -2.0 pills | Standard Deviation 4.1 |
| KYG0395 (Lower Dose Group) | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of follow-up | -2.6 pills | Standard Deviation 3.16 |
| Placebo | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of treatment | -2.0 pills | Standard Deviation 4.05 |
| Placebo | Rescue Medication Consumption at the End of Treatment and Follow-up Period | end of follow-up | -2.9 pills | Standard Deviation 3.93 |
Secondary
Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period
The subject's evaluation of overall satisfaction was recorded in the electronic subject diary at the end of the 3 treatment cycles and at the end of the 3-cycle follow-up period (at the end of the day before the subject goes to bed) using the numeric rating scale provided below: 0=None, Not satisfied with the treatment outcome； 1. Mild, Mildly satisfied with the treatment outcome； 2. Most, Mostly satisfied with the treatment outcome； 3. Complete, Completely satisfied with the treatment outcome.
Time frame: Base line and end of follow-up (9 months)
Population: Full analysis set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| KYG0395 (High Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | mild satisfaction | 18.6 percentage of complete satisfaction |
| KYG0395 (High Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | moderate satisfaction | 25.4 percentage of complete satisfaction |
| KYG0395 (High Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | complete satisfaction | 35.6 percentage of complete satisfaction |
| KYG0395 (Lower Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | mild satisfaction | 26.5 percentage of complete satisfaction |
| KYG0395 (Lower Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | complete satisfaction | 16.3 percentage of complete satisfaction |
| KYG0395 (Lower Dose Group) | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | moderate satisfaction | 49.0 percentage of complete satisfaction |
| Placebo | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | mild satisfaction | 19.4 percentage of complete satisfaction |
| Placebo | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | moderate satisfaction | 40.3 percentage of complete satisfaction |
| Placebo | Subject's Overall Satisfaction at the End of the 3-cycle Follow-up Period | complete satisfaction | 24.2 percentage of complete satisfaction |