The Safety and Efficacy of Gefapixant (AF-219/MK-7264) in Female Participants With Interstitial Cystitis /Bladder Pain Syndrome (MK-7264-005)

• ClinicalTrials.gov Identifier: NCT01569438
• Recruitment Status: Terminated
• First Posted: April 3, 2012
• Results First Posted: January 12, 2017
• Last Update Posted: August 17, 2020
• Sponsor: Afferent Pharmaceuticals, Inc.
• Information provided by (Responsible Party): Afferent Pharmaceuticals, Inc.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Bladder Pain Syndrome
• Interventions: Drug: Gefapixant; Drug: Placebo
• Enrollment: 107

Participant Flow

Recruitment Details	Overall, 107 participants were randomized (55 in Gefapixant intervention group, and 52 in Placebo group).
Pre-assignment Details	Of 107 participants randomized to the study, 105 received at least one dose of study treatment (All Treated Population) and were evaluable for all safety analysis.

Arm/Group Title	Placebo	Gefapixant
Arm/Group Description	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.
Period Title: Overall Study
Started	52	55
Treated	51	54
Titration Set	38	36
Completed	45	33
Not Completed	7	22
Reason Not Completed
Lack of Efficacy	1	2
Withdrawal by Subject	0	3
Adverse Event	2	15
Protocol Violation	2	0
Decrease of GFR greater than 30 ml/min	1	0
Sponsor/Physician decision	1	1
Unable to adhere to study schedule	0	1

Baseline Characteristics

Arm/Group Title		Gefapixant	Placebo	Total
Arm/Group Description		Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.	Total of all reporting groups
Overall Number of Baseline Participants		55	52	107
Baseline Analysis Population Description		All randomized participants
Age, Categorical; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	55 participants	52 participants	107 participants
	<=18 years	0 0.0%	0 0.0%	0 0.0%
	Between 18 and 65 years	50 90.9%	52 100.0%	102 95.3%
	>=65 years	5 9.1%	0 0.0%	5 4.7%
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	55 participants	52 participants	107 participants
	Female	55 100.0%	52 100.0%	107 100.0%
	Male	0 0.0%	0 0.0%	0 0.0%
Ethnicity (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	55 participants	52 participants	107 participants
	Hispanic or Latino	3 5.5%	0 0.0%	3 2.8%
	Not Hispanic or Latino	52 94.5%	52 100.0%	104 97.2%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	55 participants	52 participants	107 participants
	American Indian or Alaska Native	2 3.6%	0 0.0%	2 1.9%
	Asian	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%
	Black or African American	5 9.1%	6 11.5%	11 10.3%
	White	46 83.6%	46 88.5%	92 86.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	2 3.6%	0 0.0%	2 1.9%
Region of Enrollment; Measure Type: Count of Participants; Unit of measure: Participants
United States	Number Analyzed	55 participants	52 participants	107 participants
		55 100.0%	52 100.0%	107 100.0%
Numeric Pain Rating Scale (NPRS) Score [1] [2]; Mean (Standard Deviation); Unit of measure: Score on a scale
	Number Analyzed	54 participants	51 participants	105 participants
		6.20 (1.41)	6.53 (1.23)	6.36 (1.33)
		[1] Measure Description: Participants were instructed to select a number between 0 and 10 where 0 is no pain and 10 is the worst pain possible. The scale was completed by telephone (an interactive voice response system [IVRS]) every evening before bedtime. In order to qualify for study entry, participants must have had an average score of >=4 and <10 during the baseline assessment phase.; [2] Measure Analysis Population Description: NPRS score was calculated only on randomized participants who received at least had one dose of study treatment.

Outcome Measures

1. Primary Outcome

Title	Change From Baseline in the Average Mean Numeric Pain Rating Scale (NPRS) Score at Week 4
Description	The bladder pain severity was measured using 0-10 NPRS, with 0 representing 'no pain' and 10 representing 'the worst pain possible'. Participants were asked to select a number on the scale that best described the severity of bladder pain during past 24 hours over telephone using an interactive voice response system (IVRS) every evening at bedtime during the baseline assessment phase and treatment phase (up to 4 weeks). The primary analysis was conducted using a Mixed Model with Repeated Measures (MMRM) approach to calculate the Least Squares (LS) mean change from baseline in NPRS score and associated Standard Error (SE) at Week 4 for each treatment arm. Negative values indicate decrease in bladder pain severity.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Titration Completers Population - defined as participants who received at least 1 dose of drug, had at least 1 post-baseline NPRS Score, who titrated the dose in Week 1 of the treatment phase, and who completed the 4-week treatment phase

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description:	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.
Overall Number of Participants Analyzed	26	35
Least Squares Mean (Standard Error); Unit of Measure: Score on a scale
	-2.6 (0.34)	-1.9 (0.31)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments	MMRM approach was used to model the change from baseline as a function of treatment, week, treatment by week interaction, baseline score, and baseline score by week interaction.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.0734
	Comments	one-sided
	Method	Mixed Model with Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-0.7
	Confidence Interval	(2-Sided) 90%; -1.6 to 0.2
	Estimation Comments	[Not Specified]

2. Secondary Outcome

Title	Change From Baseline in Painful Bladder/Interstitial Cystitis Symptom Diary (PBIC-SD) Score at Week 4
Description	To assess the severity of bladder pain syndrome (BPS), an 8-item participant self-report PBIC-SD measure was used. Participants were asked to select a number on the scale that best described the severity of bladder pain over telephone using an IVRS each evening on the three consecutive days (during the Baseline Assessment Phase and during each Treatment Week up to 4 weeks). Each item was graded on a scale from 0 (good condition) to 4 (poor condition) with a total score range 0-32. Higher scores indicate more severe BPS. The analysis was conducted using a MMRM approach to calculate the LS mean change from baseline PBIC-SD total score and associated SE at Week 4 for each treatment arm. Negative values indicate decrease in severity of BPS.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Titration Completers Population - defined as participants who received at least 1 dose of drug, had at least 1 post-baseline PBIC-SD Score, who titrated the dose in Week 1 of the treatment phase, and who completed the 4-week treatment phase.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description:	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.
Overall Number of Participants Analyzed	27	36
Least Squares Mean (Standard Error); Unit of Measure: Score on a scale
	-7.8 (1.29)	-6.7 (1.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments	MMRM approach was used to model the change from baseline as a function of treatment, week, treatment by week interaction, baseline score, and baseline score by week interaction.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.2726
	Comments	one-sided
	Method	Mixed Model With Repeated Measures
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-1.0
	Confidence Interval	(2-Sided) 90%; -3.9 to 1.8
	Estimation Comments	[Not Specified]

3. Secondary Outcome

Title	Change From Baseline in O'Leary-Sant Interstitial Cystitis Symptom Index (ICSI) Score at Week 4
Description	To measure the severity of BPS (urgency and frequency of urination, nighttime urination, and pain or burning) over past month, a 4-item self-report ICSI measure was used. Participants were asked to select a number on the scale that best described the severity of symptoms over telephone using an IVRS every evening at bedtime during the baseline assessment phase and treatment phase (up to 4 weeks). The ICSI score range from 0 (Not at all) to 5 (Almost always) for the first 3 items and a score of 0 (Not at all) to 4 (Almost always) for the last item, with an index score range of 0-19. Higher scores indicate more severe BPS. The analysis was conducted using one-way ANCOVA model to calculate the LS mean change from baseline ICSI total score and associated SE at Week 4 for each treatment arm. Negative values indicate decrease in severity of BPS.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Titration Completers Population - defined as participants who received at least 1 dose of drug, had at least 1 post-baseline ICSI Score, who titrated the dose in Week 1 of the treatment phase, and who completed the 4-week treatment phase.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description:	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.
Overall Number of Participants Analyzed	35	38
Least Squares Mean (Standard Error); Unit of Measure: Score on a scale
	-3.8 (0.62)	-3.4 (0.60)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments	The one-way ANCOVA model was used to calculate change from baseline as a function of treatment and baseline score.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.3603
	Comments	one-sided
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-0.3
	Confidence Interval	(2-Sided) 90%; -1.7 to 1.1
	Estimation Comments	[Not Specified]

4. Secondary Outcome

Title	Change From Baseline in Genitourinary Pain Index (GUPI) Score at Week 4
Description	To measure the degree of genitourinary pain symptoms, an 8-item self-report GUPI measure was used. Participants were asked to select a number on the scale that best described the severity of symptoms over telephone using an IVRS every evening at bedtime during the baseline assessment phase and treatment phase (up to 4 weeks). The GUPI instrument yields a total score of 0-45 and 3 subscales: pain (score = 0-23), urinary (score = 0-10), and quality of life (score = 0-12). Higher scores indicate more severe symptoms. The analysis was conducted using one-way ANCOVA model to calculate the LS mean change from baseline GUPI total score and associated SE at Week 4 for each treatment arm. Negative values indicate decrease in degree of genitourinary pain symptoms.
Time Frame	Baseline and Week 4

Outcome Measure Data

Analysis Population Description

Titration Completers Population - defined as participants who received at least 1 dose of drug, had at least 1 post-baseline GUPI Score, who titrated the dose in Week 1 of the treatment phase, and who completed the 4-week treatment phase.

Arm/Group Title	Gefapixant	Placebo
Arm/Group Description:	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.
Overall Number of Participants Analyzed	34	36
Least Squares Mean (Standard Error); Unit of Measure: Score on a scale
	-5.1 (0.88)	-3.7 (0.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Gefapixant, Placebo
	Comments	The one-way ANCOVA model was used to calculate change from baseline as a function of treatment and baseline score.
	Type of Statistical Test	Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	0.1183
	Comments	one-sided
	Method	ANCOVA
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Mean Difference
	Estimated Value	-1.5
	Confidence Interval	(2-Sided) 90%; -3.5 to 0.6
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Up to approximately 6 weeks
Adverse Event Reporting Description	All-Cause Mortality reported for all randomized participants. Serious Adverse Events (SAEs) and Other Adverse Events (AEs) were reported for all participants who received at least 1 dose of study treatment.
Arm/Group Title	Placebo	Gefapixant
Arm/Group Description	Female participants receive dose matched placebo tablets, twice daily (BID), orally, with food for 4 weeks.	Female participants receive gefapixant, a total dose titrated from 50 mg to highest tolerated dose (maximum of 300 mg) twice daily (BID), orally over a period of 6 days with food depending on safety and tolerability, and then maintain that dose for the course of a 4-week treatment period. Participants were allowed to decrease the dose if tolerability issues occurred.
All-Cause Mortality
	Placebo	Gefapixant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/52 (0.00%)	0/55 (0.00%)
Serious Adverse Events
	Placebo	Gefapixant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/51 (0.00%)	0/54 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Placebo	Gefapixant
	Affected / at Risk (%)	Affected / at Risk (%)
Total	36/51 (70.59%)	53/54 (98.15%)
Gastrointestinal disorders
Nausea † 1	10/51 (19.61%)	10/54 (18.52%)
Dry mouth † 1	2/51 (3.92%)	7/54 (12.96%)
Paraesthesia oral † 1	0/51 (0.00%)	7/54 (12.96%)
Salivary hypersecretion † 1	0/51 (0.00%)	6/54 (11.11%)
Vomiting † 1	1/51 (1.96%)	5/54 (9.26%)
Hypoaesthesia oral † 1	3/51 (5.88%)	3/54 (5.56%)
Diarrhoea † 1	1/51 (1.96%)	3/54 (5.56%)
Abdominal pain † 1	0/51 (0.00%)	3/54 (5.56%)
Infections and infestations
Urinary tract infection † 1	1/51 (1.96%)	3/54 (5.56%)
Investigations
Urine output decreased † 1	1/51 (1.96%)	7/54 (12.96%)
Metabolism and nutrition disorders
Decreased appetite † 1	0/51 (0.00%)	7/54 (12.96%)
Musculoskeletal and connective tissue disorders
Flank pain † 1	7/51 (13.73%)	2/54 (3.70%)
Arthralgia † 1	3/51 (5.88%)	0/54 (0.00%)
Nervous system disorders
Dysgeusia † 1	9/51 (17.65%)	38/54 (70.37%)
Headache † 1	6/51 (11.76%)	5/54 (9.26%)
Ageusia † 1	0/51 (0.00%)	7/54 (12.96%)
Hypogeusia † 1	0/51 (0.00%)	3/54 (5.56%)
Renal and urinary disorders
Pollakiuria † 1	3/51 (5.88%)	5/54 (9.26%)
Dysuria † 1	1/51 (1.96%)	4/54 (7.41%)
Bladder pain † 1	3/51 (5.88%)	2/54 (3.70%)
Respiratory, thoracic and mediastinal disorders
Cough † 1	1/51 (1.96%)	7/54 (12.96%)
Dry throat † 1	2/51 (3.92%)	3/54 (5.56%)
Throat irritation † 1	1/51 (1.96%)	3/54 (5.56%)
1 Term from vocabulary, MedDRA 14.0; † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

60 days prior to the submission of any results, the PI shall submit to SPONSOR any proposed PUBLICATION, which period may be extended for an additional 30 days if requested by SPONSOR. If any Confidential Information should be redacted or patent applications relating to an Invention should be filed prior to PUBLICATION, then PUBLICATION will be delayed until patent application has been filed. Delay of a PUBLICATION shall not exceed 24 months from the date of such notice to the PI.

Results Point of Contact

• Name/Title: Senior Vice President, Global Clinical Development
• Organization: Merck Sharp & Dohme Corp.
• Phone: 1-800-672-6372
• EMail: ClinicalTrialsDisclosure@merck.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Imamura M, Scott NW, Wallace SA, Ogah JA, Ford AA, Dubos YA, Brazzelli M. Interventions for treating people with symptoms of bladder pain syndrome: a network meta-analysis. Cochrane Database Syst Rev. 2020 Jul 30;7:CD013325. doi: 10.1002/14651858.CD013325.pub2.

• Responsible Party: Afferent Pharmaceuticals, Inc.
• ClinicalTrials.gov Identifier: NCT01569438
• Other Study ID Numbers: 7264-005; AF219-005 ( Other Identifier: Afferent Pharmaceuticals ); MK-7264-005 ( Other Identifier: Merck Protocol Number )
• First Submitted: March 30, 2012
• First Posted: April 3, 2012
• Results First Submitted: September 23, 2016
• Results First Posted: January 12, 2017
• Last Update Posted: August 17, 2020