Trial Outcomes & Findings for Traditional Clomiphene Citrate Administration vs. Stair-step Approach (NCT NCT01008319)

NCT ID: NCT01008319

Last Updated: 2018-01-08

Results Overview

We hypothesized that time to ovulation would be shorter with stair-step protocol vs. traditional.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 120 participants
• Primary outcome timeframe: 5 years
• Results posted on: 2018-01-08

Participant Flow

Recruitment was in the infertility clinic.

Participant milestones

Measure	Traditional Administration The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 5). If ovulation does not occur by day 21 then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg).	Stair-Step Administration The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Overall Study STARTED	60	60
Overall Study COMPLETED	60	60
Overall Study NOT COMPLETED	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Traditional Clomiphene Citrate Administration vs. Stair-step Approach

Baseline characteristics by cohort

Measure	Traditional Administration n=60 Participants	Stair-Step Administration n=60 Participants	Total n=120 Participants Total of all reporting groups
Age, Continuous	27.88 years STANDARD_DEVIATION 4.95 • n=5 Participants	29.37 years STANDARD_DEVIATION 3.96 • n=7 Participants	28.65 years STANDARD_DEVIATION 4.45 • n=5 Participants
Sex: Female, Male Female	60 Participants n=5 Participants	60 Participants n=7 Participants	120 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	4 Participants n=5 Participants	0 Participants n=7 Participants	4 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	6 Participants n=5 Participants	3 Participants n=7 Participants	9 Participants n=5 Participants
Race (NIH/OMB) White	46 Participants n=5 Participants	55 Participants n=7 Participants	101 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 5 years

We hypothesized that time to ovulation would be shorter with stair-step protocol vs. traditional.

Outcome measures

Measure	Traditional Administration n=60 Participants The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 3, 4, or 5). If ovulation does not occur then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. clomiphene citrate: Clomiphene citrate 50 mg for 5 days starting on cycle day 5. Transvaginal ultrasound between cycle days 11 to 14 to determine if there is a dominant follicle. If NO dominant follicle present, another ultrasound and blood draw (to test progesterone level) will be done one week later to confirm no response to the medication dose. Medroxyprogesterone acetate (Provera) 10 mg per day for 10 days. Increased dose of clomiphene citrate for 5 days starting on cycle day 5. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg) until a dominant follicle(s) is present.	Stair-Step Administration n=60 Participants The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This would eliminate the days of progestin (10 days) and the waiting for the period (usually 3 to 7 days) and finally waiting to start clomiphene citrate on cycle day 3 at the earliest (3 more days) for a total of up to 20 days difference for the 100 mg dose of clomid. If they did not ovulate on 100mg, then the process repeats and another 20 days before they start 150mg. Therefore, the time to ovulation and pregnancy may be reduced, and hopefully pregnancy, by using the stair-step protocol. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Time to Ovulation With Each Protocol	31.1 days Standard Error 3.5	21.5 days Standard Error 0.9

SECONDARY outcome

Timeframe: 5 years

Population: Proportion of subjects that ovulated at each dose of Clomid based on which protocol they were randomized to.

Rate of ovulation with each dose of clomid within each protocol

Outcome measures

Measure	Traditional Administration n=60 Participants The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 3, 4, or 5). If ovulation does not occur then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. clomiphene citrate: Clomiphene citrate 50 mg for 5 days starting on cycle day 5. Transvaginal ultrasound between cycle days 11 to 14 to determine if there is a dominant follicle. If NO dominant follicle present, another ultrasound and blood draw (to test progesterone level) will be done one week later to confirm no response to the medication dose. Medroxyprogesterone acetate (Provera) 10 mg per day for 10 days. Increased dose of clomiphene citrate for 5 days starting on cycle day 5. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg) until a dominant follicle(s) is present.	Stair-Step Administration n=60 Participants The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This would eliminate the days of progestin (10 days) and the waiting for the period (usually 3 to 7 days) and finally waiting to start clomiphene citrate on cycle day 3 at the earliest (3 more days) for a total of up to 20 days difference for the 100 mg dose of clomid. If they did not ovulate on 100mg, then the process repeats and another 20 days before they start 150mg. Therefore, the time to ovulation and pregnancy may be reduced, and hopefully pregnancy, by using the stair-step protocol. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Rate of Ovulation Clomid 50mg	45 Participants	26 Participants
Rate of Ovulation Clomid 100mg	7 Participants	18 Participants
Rate of Ovulation Clomid 150mg	1 Participants	10 Participants
Rate of Ovulation Clomid No Response	7 Participants	6 Participants

SECONDARY outcome

Timeframe: 5 years

Population: Number of participants randomized to each arm.

Proportion of participants that delivered a baby based on which protocol they were randomized to.

Outcome measures

Measure	Traditional Administration n=60 Participants The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 3, 4, or 5). If ovulation does not occur then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. clomiphene citrate: Clomiphene citrate 50 mg for 5 days starting on cycle day 5. Transvaginal ultrasound between cycle days 11 to 14 to determine if there is a dominant follicle. If NO dominant follicle present, another ultrasound and blood draw (to test progesterone level) will be done one week later to confirm no response to the medication dose. Medroxyprogesterone acetate (Provera) 10 mg per day for 10 days. Increased dose of clomiphene citrate for 5 days starting on cycle day 5. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg) until a dominant follicle(s) is present.	Stair-Step Administration n=60 Participants The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This would eliminate the days of progestin (10 days) and the waiting for the period (usually 3 to 7 days) and finally waiting to start clomiphene citrate on cycle day 3 at the earliest (3 more days) for a total of up to 20 days difference for the 100 mg dose of clomid. If they did not ovulate on 100mg, then the process repeats and another 20 days before they start 150mg. Therefore, the time to ovulation and pregnancy may be reduced, and hopefully pregnancy, by using the stair-step protocol. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Delivery Outcomes	21 Participants	21 Participants

Adverse Events

Traditional Administration

Serious events: 2 serious events

Other events: 60 other events

Deaths: 0 deaths

Stair-Step Administration

Serious events: 3 serious events

Other events: 60 other events

Deaths: 0 deaths

Serious adverse events

Measure	Traditional Administration n=60 participants at risk The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 3, 4, or 5). If ovulation does not occur then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. clomiphene citrate: Clomiphene citrate 50 mg for 5 days starting on cycle day 5. Transvaginal ultrasound between cycle days 11 to 14 to determine if there is a dominant follicle. If NO dominant follicle present, another ultrasound and blood draw (to test progesterone level) will be done one week later to confirm no response to the medication dose. Medroxyprogesterone acetate (Provera) 10 mg per day for 10 days. Increased dose of clomiphene citrate for 5 days starting on cycle day 5. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg) until a dominant follicle(s) is present.	Stair-Step Administration n=60 participants at risk The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This would eliminate the days of progestin (10 days) and the waiting for the period (usually 3 to 7 days) and finally waiting to start clomiphene citrate on cycle day 3 at the earliest (3 more days) for a total of up to 20 days difference for the 100 mg dose of clomid. If they did not ovulate on 100mg, then the process repeats and another 20 days before they start 150mg. Therefore, the time to ovulation and pregnancy may be reduced, and hopefully pregnancy, by using the stair-step protocol. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Congenital, familial and genetic disorders Birth Defect	0.00% 0/60 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	3.3% 2/60 • Number of events 2 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Eye disorders Blurry Vision/Double Vision	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Hepatobiliary disorders Gallstones	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	0.00% 0/60 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.

Other adverse events

Measure	Traditional Administration n=60 participants at risk The traditional approach to ovulation induction with clomiphene citrate involves administration of 50mg/day for five days (starting on cycle day 3, 4, or 5). If ovulation does not occur then a progestin is prescribed to induce menses (which occurs within one week of stopping the progestin) and then a higher dose of medication is used in the next cycle. clomiphene citrate: Clomiphene citrate 50 mg for 5 days starting on cycle day 5. Transvaginal ultrasound between cycle days 11 to 14 to determine if there is a dominant follicle. If NO dominant follicle present, another ultrasound and blood draw (to test progesterone level) will be done one week later to confirm no response to the medication dose. Medroxyprogesterone acetate (Provera) 10 mg per day for 10 days. Increased dose of clomiphene citrate for 5 days starting on cycle day 5. This process will be repeated at increased doses of clomiphene citrate (100 mg and 150 mg) until a dominant follicle(s) is present.	Stair-Step Administration n=60 participants at risk The stair-step protocol the dose of clomiphene citrate would be increased without administering progestin and inducing a period. This would eliminate the days of progestin (10 days) and the waiting for the period (usually 3 to 7 days) and finally waiting to start clomiphene citrate on cycle day 3 at the earliest (3 more days) for a total of up to 20 days difference for the 100 mg dose of clomid. If they did not ovulate on 100mg, then the process repeats and another 20 days before they start 150mg. Therefore, the time to ovulation and pregnancy may be reduced, and hopefully pregnancy, by using the stair-step protocol. This method utilizes ultrasound monitoring for follicle development before increasing the dose of clomiphene citrate.
Endocrine disorders Vasomotor Flushes (hot flashes)	53.3% 32/60 • Number of events 146 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	50.0% 30/60 • Number of events 83 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Psychiatric disorders Mood Swings	53.3% 32/60 • Number of events 104 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	45.0% 27/60 • Number of events 67 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Reproductive system and breast disorders Breast tenderness	35.0% 21/60 • Number of events 35 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	35.0% 21/60 • Number of events 30 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Reproductive system and breast disorders Pelvic Discomfort	48.3% 29/60 • Number of events 75 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	30.0% 18/60 • Number of events 36 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Gastrointestinal disorders Nausea	43.3% 26/60 • Number of events 48 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	25.0% 15/60 • Number of events 28 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Eye disorders Blurry Vision/Double Vision	10.0% 6/60 • Number of events 9 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	5.0% 3/60 • Number of events 3 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Eye disorders Light sensitivity	11.7% 7/60 • Number of events 19 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	1.7% 1/60 • Number of events 2 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Nervous system disorders Headaches	56.7% 34/60 • Number of events 90 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	45.0% 27/60 • Number of events 53 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Gastrointestinal disorders Vomiting	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Renal and urinary disorders Decreased urination frequency	0.00% 0/60 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	1.7% 1/60 • Number of events 1 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Endocrine disorders Weight gain	18.3% 11/60 • Number of events 21 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	10.0% 6/60 • Number of events 9 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
General disorders Insomnia	25.0% 15/60 • Number of events 33 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	11.7% 7/60 • Number of events 13 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Psychiatric disorders Nervousness	20.0% 12/60 • Number of events 21 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	5.0% 3/60 • Number of events 4 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.
Musculoskeletal and connective tissue disorders Leg pain/leg swelling	6.7% 4/60 • Number of events 6 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.	3.3% 2/60 • Number of events 2 Questionnaire were administered at each appointment for ultrasound evaluation. They assessed none, mild, moderate or severe symptoms including: hot flashes, mood swings, breast tenderness, pelvic discomfort, nausea, vomiting, blurry vision, light sensitivity, headache, decreased urination, weight gain, insomnia, nervousness and leg pain.

Additional Information

LaTasha Craig, MD

University of Oklahoma

Phone: 405-271-8787

Email: latasha-craig@ouhsc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place