Back to resultsInvestigation of the Superiority Effect of Desmopressin to Placebo in Terms of Night Voids Reduction in Nocturia Adult Female Patients (COMFORT)
Primary Purpose
Nocturia
Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Desmopressin
Placebo
Sponsored by
About this trial
This is an interventional treatment trial for Nocturia
Eligibility Criteria
Inclusion Criteria:
- Written informed consent prior to performance of any trial-related activity
- Female sex 18 years of age or older
- At least 2 voids every night in a consecutive 3-day period during the screening period
Exclusion Criteria:
Evidence of severe daytime voiding dysfunction defined as:
- Urge urinary incontinence (more than 1 episode/day in the 3-day diary period)
- Urgency (more than 1 episode/day in the 3-day diary period)
- Frequency (more than 8 daytime voids/day in the 3-day diary period)
- Interstitial cystitis
- Urinary retention or a post void residual volume in excess of 150 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention
- Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours)
- Central or nephrogenic diabetes insipidus
- Syndrome of inappropriate anti-diuretic hormone secretion
- Current or a history of urologic malignancies e.g. bladder cancer
- Genitourinary tract pathology e.g., infection or stone in the bladder and urethra causing symptoms
- Neurogenic detrusor activity (detrusor overactivity).
- Suspicion or evidence of cardiac failure
- Uncontrolled hypertension
- Uncontrolled diabetes mellitus
- Hyponatraemia: Serum sodium level must be within normal limits
- Renal insufficiency: Serum creatinine must be within normal limits and estimated glomerular filtration rate must be more than or equal to 50 mL/min
- Hepatic and/or biliary diseases: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels must not be more than twice the upper limit of normal range. Total bilirubin level must not be more than 1.5 mg/dL
- History of obstructive sleep apnea
- Previous desmopressin treatment for nocturia
- Treatment with another investigational product within 3 months prior to screening
- Concomitant treatment with any prohibited medication e.g., loop diuretics (furosemide, torsemide, ethacrynic acid) and any other investigational drug
- Pregnancy, breastfeeding, or a plan to become pregnant during the period of the clinical trial. Subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal subjects have to perform pregnancy tests. Amenorrhea of more than 12 months' duration based on the reported date of the last menstrual period is sufficient documentation of post-menopausal status and does not require a pregnancy test
- Known alcohol or substance abuse
- Work or lifestyle that may interfere with regular nighttime sleep e.g., shift workers
- Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the Investigator, would impair participation in the trial
Sites / Locations
- Medical Affiliated Research Center Inc.
- Radiant Research Inc.
- Family Medical Center
- Axis Clinical Trials
- Radiant Research Inc.
- Downtown Woman's Health Care
- Front Range Clinical Research
- South Florida Medical Research
- Women's Medical Research Group, LLC
- Avail Clinical Research, LLC
- FPA Clinical Research
- Sunrise Medical Research
- DMI Research
- Southeastern Institute
- Southeastern Medical Research Institute
- Radiant Research Inc.
- NorthShore University HealthSystem
- Accelovance
- Accelovance
- FutureCare Studies
- Bay State Clinical Trials, Inc.
- Beyer Research
- Remedica, LLC
- Radiant Research, Inc.
- Radiant Research, Inc.
- Radiant Research
- Anderson & Collins Clinical Research Inc
- ACCUMED Research Associates
- Center for Urologic Research of WNY, LLC
- Radiant Research, Inc.
- Community Research
- Complete HealthCare for Women
- HWC Women's Research Center
- Urologic Consultants of SE PA
- Philadelphia Clinical Research, LLC
- Radiant Research, Inc.
- Carolina Urologic Research Center
- Radiant Research Inc.
- Quality Research, Inc.
- Radiant Research, Inc.
- Exemplar Research Inc.
- CanMed Clinical Research Inc.
- The Male/Female Health Research Center
- Urology Associates/Urologic Medical Research
- Investigational site
Arms of the Study
Arm 1
Arm 2
Arm Type
Experimental
Placebo Comparator
Arm Label
Desmopressin 25 μg
Placebo
Arm Description
Participants took 1 orally disintegrating tablet of desmopressin 25 μg every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.
Participants took 1 orally disintegrating tablet of placebo every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.
Outcomes
Primary Outcome Measures
Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period
The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Change from baseline values for Week 1, and Months 1, 2 and 3 are reported below.
Comparison of the mean number of nocturnal voids at baseline and over a 3-month treatment period (obtained by longitudinal analysis of Week 1, and Months 1, 2 and 3) are reported in the statistical analysis. This was the first co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3
Probability of participants achieving 33% responder status during 3 months of treatment employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
This was the second co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.
Secondary Outcome Measures
Change From Baseline in Mean Number of Nocturnal Voids at Month 3
The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Month 3 for this outcome) as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
Secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3
Probability of participants achieving 33% responder status at Month 3 employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the Month 3 visit as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Change From Baseline in Mean Time to First Nocturnal Void at Month 3
The time to first void was defined as the time from going to bed with the intention of sleeping until first nocturnal void or until waking in the morning in cases where there was no nocturnal void. The time to first void was derived from the sleep and voiding diary. The mean time to first void was calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Change From Baseline in Nocturnal Urine Volume at Month 3
The nocturnal urine volume was derived from the 3-day urine volume diary. The nocturnal urine volume included the volume of the first morning void. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Change From Baseline in 24-Hour Urine Volume at Month 3
Twenty-four hour urine volume was derived from the 3-day urine volume diary. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Summary of Participants With Treatment-Emergent Adverse Events (TEAEs)
A TEAE was any adverse event occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day of the last dose of desmopressin. An adverse drug reaction (ADR) was any AE assessed by the Investigator as possibly/probably related to study drug.
Minimum Post-Treatment Serum Sodium Levels
Serum sodium levels were monitored since hyponatremia is a potential serious adverse event associated with daily doses of desmopressin. The serum sodium level must have been within the normal reference range at the Screening Visit for the participant to be eligible for enrollment. A participant was to be withdrawn from the trial if the serum sodium level was <=125 mmol/L at any time.
Full Information
NCT ID
NCT01223937
First Posted
October 18, 2010
Last Updated
September 16, 2015
Sponsor
Ferring Pharmaceuticals
1. Study Identification
Unique Protocol Identification Number
NCT01223937
Brief Title
Investigation of the Superiority Effect of Desmopressin to Placebo in Terms of Night Voids Reduction in Nocturia Adult Female Patients
Acronym
COMFORT
Official Title
A Multi-centre, Randomised, Double-blind, Placebo-controlled, Parallel-group Trial to Demonstrate the Efficacy and Safety of Desmopressin Orally Disintegrating Tablet for the Treatment of Nocturia in Adult Females
Study Type
Interventional
2. Study Status
Record Verification Date
September 2015
Overall Recruitment Status
Completed
Study Start Date
November 2010 (undefined)
Primary Completion Date
November 2011 (Actual)
Study Completion Date
November 2011 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Ferring Pharmaceuticals
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
A multicenter, randomized, double-blind, placebo-controlled, parallel-group trial to investigate the safety and efficacy of desmopressin oral melt tablets against placebo during 3 months of treatment in adult females with nocturia.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Nocturia
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
268 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Desmopressin 25 μg
Arm Type
Experimental
Arm Description
Participants took 1 orally disintegrating tablet of desmopressin 25 μg every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Participants took 1 orally disintegrating tablet of placebo every night approximately 1 hour before bedtime for the entire duration of the 3-month treatment period.
Intervention Type
Drug
Intervention Name(s)
Desmopressin
Other Intervention Name(s)
FE992026, MINIRIN®, Nocturin®
Intervention Type
Drug
Intervention Name(s)
Placebo
Primary Outcome Measure Information:
Title
Change From Baseline in Mean Number of Nocturnal Voids Averaged Over a 3-Month Period
Description
The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void. Change from baseline values for Week 1, and Months 1, 2 and 3 are reported below.
Comparison of the mean number of nocturnal voids at baseline and over a 3-month treatment period (obtained by longitudinal analysis of Week 1, and Months 1, 2 and 3) are reported in the statistical analysis. This was the first co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.
Time Frame
Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)
Title
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids for All During-Treatment Visits up to Month 3
Description
Probability of participants achieving 33% responder status during 3 months of treatment employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during treatment visits (Week 1, Months 1, 2, 3) as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
This was the second co-primary endpoint. The trial was to be declared positive only if the 25 μg desmopressin group had a statistically significant positive effect as compared to placebo on both co-primary endpoints.
Time Frame
Day 1 (Baseline); Week 1, Months 1, 2, 3 (3-month treatment period)
Secondary Outcome Measure Information:
Title
Change From Baseline in Mean Number of Nocturnal Voids at Month 3
Description
The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the during-treatment visits (Month 3 for this outcome) as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
Secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Time Frame
Day 1 (Baseline), Month 3
Title
Adjusted Probability of Participants Achieving a >33% Reduction From Baseline in Number of Nocturnal Voids at Month 3
Description
Probability of participants achieving 33% responder status at Month 3 employed a longitudinal analysis assessing nocturnal void information captured in the 3-day diary. A 33% responder was defined as a participant with a decrease of at least 33% in the mean number of nocturnal voids relative to baseline. The number of nocturnal voids was the average over 3 consecutive 24-hour periods prior to Day 1 and prior to the Month 3 visit as recorded in participant diaries. The first morning void was not counted as a nocturnal void.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Time Frame
Day 1 (Baseline), Month 3
Title
Change From Baseline in Mean Time to First Nocturnal Void at Month 3
Description
The time to first void was defined as the time from going to bed with the intention of sleeping until first nocturnal void or until waking in the morning in cases where there was no nocturnal void. The time to first void was derived from the sleep and voiding diary. The mean time to first void was calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Time Frame
Day 1 (Baseline), Month 3
Title
Change From Baseline in Nocturnal Urine Volume at Month 3
Description
The nocturnal urine volume was derived from the 3-day urine volume diary. The nocturnal urine volume included the volume of the first morning void. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Time Frame
Day 1 (Baseline), Month 3
Title
Change From Baseline in 24-Hour Urine Volume at Month 3
Description
Twenty-four hour urine volume was derived from the 3-day urine volume diary. Mean urine volumes were calculated as the average over 3 consecutive 24-hour periods prior to the Month 3 visit.
The secondary efficacy outcomes (#3-7) used a hierarchical step-down approach in the order listed.
Time Frame
Day 1 (Baseline), Month 3
Title
Summary of Participants With Treatment-Emergent Adverse Events (TEAEs)
Description
A TEAE was any adverse event occurring after start of treatment and within the time of residual drug effect, i.e., within 1 day of the last dose of desmopressin. An adverse drug reaction (ADR) was any AE assessed by the Investigator as possibly/probably related to study drug.
Time Frame
Day 1 up to 3 months
Title
Minimum Post-Treatment Serum Sodium Levels
Description
Serum sodium levels were monitored since hyponatremia is a potential serious adverse event associated with daily doses of desmopressin. The serum sodium level must have been within the normal reference range at the Screening Visit for the participant to be eligible for enrollment. A participant was to be withdrawn from the trial if the serum sodium level was <=125 mmol/L at any time.
Time Frame
Day 1 up to 3 months
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Written informed consent prior to performance of any trial-related activity
Female sex 18 years of age or older
At least 2 voids every night in a consecutive 3-day period during the screening period
Exclusion Criteria:
Evidence of severe daytime voiding dysfunction defined as:
Urge urinary incontinence (more than 1 episode/day in the 3-day diary period)
Urgency (more than 1 episode/day in the 3-day diary period)
Frequency (more than 8 daytime voids/day in the 3-day diary period)
Interstitial cystitis
Urinary retention or a post void residual volume in excess of 150 mL as confirmed by bladder ultrasound performed after suspicion of urinary retention
Habitual or psychogenic polydipsia (fluid intake resulting in a urine production exceeding 40 mL/kg/24 hours)
Central or nephrogenic diabetes insipidus
Syndrome of inappropriate anti-diuretic hormone secretion
Current or a history of urologic malignancies e.g. bladder cancer
Genitourinary tract pathology e.g., infection or stone in the bladder and urethra causing symptoms
Neurogenic detrusor activity (detrusor overactivity).
Suspicion or evidence of cardiac failure
Uncontrolled hypertension
Uncontrolled diabetes mellitus
Hyponatraemia: Serum sodium level must be within normal limits
Renal insufficiency: Serum creatinine must be within normal limits and estimated glomerular filtration rate must be more than or equal to 50 mL/min
Hepatic and/or biliary diseases: Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels must not be more than twice the upper limit of normal range. Total bilirubin level must not be more than 1.5 mg/dL
History of obstructive sleep apnea
Previous desmopressin treatment for nocturia
Treatment with another investigational product within 3 months prior to screening
Concomitant treatment with any prohibited medication e.g., loop diuretics (furosemide, torsemide, ethacrynic acid) and any other investigational drug
Pregnancy, breastfeeding, or a plan to become pregnant during the period of the clinical trial. Subjects of reproductive age must have documentation of a reliable method of contraception. All pre-and perimenopausal subjects have to perform pregnancy tests. Amenorrhea of more than 12 months' duration based on the reported date of the last menstrual period is sufficient documentation of post-menopausal status and does not require a pregnancy test
Known alcohol or substance abuse
Work or lifestyle that may interfere with regular nighttime sleep e.g., shift workers
Any other medical condition, laboratory abnormality, psychiatric condition, mental incapacity, or language barrier that, in the judgment of the Investigator, would impair participation in the trial
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Development Support
Organizational Affiliation
Ferring Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Medical Affiliated Research Center Inc.
City
Huntsville
State/Province
Alabama
Country
United States
Facility Name
Radiant Research Inc.
City
Scottsdale
State/Province
Arkansas
Country
United States
Facility Name
Family Medical Center
City
Foothill Ranch
State/Province
California
Country
United States
Facility Name
Axis Clinical Trials
City
Los Angeles
State/Province
California
Country
United States
Facility Name
Radiant Research Inc.
City
Santa Rosa
State/Province
California
Country
United States
Facility Name
Downtown Woman's Health Care
City
Denver
State/Province
Colorado
Country
United States
Facility Name
Front Range Clinical Research
City
Wheatridge
State/Province
Colorado
Country
United States
Facility Name
South Florida Medical Research
City
Aventura
State/Province
Florida
Country
United States
Facility Name
Women's Medical Research Group, LLC
City
Clearwater
State/Province
Florida
Country
United States
Facility Name
Avail Clinical Research, LLC
City
DeLand
State/Province
Florida
Country
United States
Facility Name
FPA Clinical Research
City
Kissimmee
State/Province
Florida
Country
United States
Facility Name
Sunrise Medical Research
City
Lauderdale Lakes
State/Province
Florida
Country
United States
Facility Name
DMI Research
City
Pinellas Park
State/Province
Florida
Country
United States
Facility Name
Southeastern Institute
City
Columbus
State/Province
Georgia
Country
United States
Facility Name
Southeastern Medical Research Institute
City
Columbus
State/Province
Georgia
Country
United States
Facility Name
Radiant Research Inc.
City
Chicago
State/Province
Illinois
Country
United States
Facility Name
NorthShore University HealthSystem
City
Evanston
State/Province
Illinois
Country
United States
Facility Name
Accelovance
City
Peoria
State/Province
Illinois
Country
United States
Facility Name
Accelovance
City
South Bend
State/Province
Indiana
Country
United States
Facility Name
FutureCare Studies
City
Springfield
State/Province
Massachusetts
Country
United States
Facility Name
Bay State Clinical Trials, Inc.
City
Watertown
State/Province
Massachusetts
Country
United States
Facility Name
Beyer Research
City
Paw Paw
State/Province
Michigan
Country
United States
Facility Name
Remedica, LLC
City
Rochester
State/Province
Michigan
Country
United States
Facility Name
Radiant Research, Inc.
City
Edina
State/Province
Minnesota
Country
United States
Facility Name
Radiant Research, Inc.
City
St. Louis
State/Province
Missouri
Country
United States
Facility Name
Radiant Research
City
Las Vegas
State/Province
Nevada
Country
United States
Facility Name
Anderson & Collins Clinical Research Inc
City
Edison
State/Province
New Jersey
Country
United States
Facility Name
ACCUMED Research Associates
City
Garden City
State/Province
New York
Country
United States
Facility Name
Center for Urologic Research of WNY, LLC
City
Williamsville
State/Province
New York
Country
United States
Facility Name
Radiant Research, Inc.
City
Akron
State/Province
Ohio
Country
United States
Facility Name
Community Research
City
Cincinnati
State/Province
Ohio
Country
United States
Facility Name
Complete HealthCare for Women
City
Columbus
State/Province
Ohio
Country
United States
Facility Name
HWC Women's Research Center
City
Englewood
State/Province
Ohio
Country
United States
Facility Name
Urologic Consultants of SE PA
City
Bala Cynwyd
State/Province
Pennsylvania
Country
United States
Facility Name
Philadelphia Clinical Research, LLC
City
Philadelphia
State/Province
Pennsylvania
Country
United States
Facility Name
Radiant Research, Inc.
City
Greer
State/Province
South Carolina
Country
United States
Facility Name
Carolina Urologic Research Center
City
Myrtle Beach
State/Province
South Carolina
Country
United States
Facility Name
Radiant Research Inc.
City
Dallas
State/Province
Texas
Country
United States
Facility Name
Quality Research, Inc.
City
San Antonio
State/Province
Texas
Country
United States
Facility Name
Radiant Research, Inc.
City
San Antonio
State/Province
Texas
Country
United States
Facility Name
Exemplar Research Inc.
City
Morgantown
State/Province
West Virginia
Country
United States
Facility Name
CanMed Clinical Research Inc.
City
Victoria
State/Province
British Columbia
Country
Canada
Facility Name
The Male/Female Health Research Center
City
Barrie
State/Province
Ontario
Country
Canada
Facility Name
Urology Associates/Urologic Medical Research
City
Kitchener
State/Province
Ontario
Country
Canada
Facility Name
Investigational site
City
North Bay
State/Province
Ontario
Country
Canada
12. IPD Sharing Statement
Citations:
PubMed Identifier
23454404
Citation
Sand PK, Dmochowski RR, Reddy J, van der Meulen EA. Efficacy and safety of low dose desmopressin orally disintegrating tablet in women with nocturia: results of a multicenter, randomized, double-blind, placebo controlled, parallel group study. J Urol. 2013 Sep;190(3):958-64. doi: 10.1016/j.juro.2013.02.037. Epub 2013 Feb 20.
Results Reference
result
PubMed Identifier
27862898
Citation
Juul KV, Malmberg A, van der Meulen E, Walle JV, Norgaard JP. Low-dose desmopressin combined with serum sodium monitoring can prevent clinically significant hyponatraemia in patients treated for nocturia. BJU Int. 2017 May;119(5):776-784. doi: 10.1111/bju.13718. Epub 2016 Dec 10.
Results Reference
derived
Learn more about this trial
Investigation of the Superiority Effect of Desmopressin to Placebo in Terms of Night Voids Reduction in Nocturia Adult Female Patients
We'll reach out to this number within 24 hrs