PCOS: Study of Pharmacodynamics of LIK066 in Overweight and Obese Women With Polycystic Ovary Syndrome

• Sponsor: Novartis Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03152591
• Collaborator: (none)
• Enrollment: 29
• Locations: 5
• Arms: 2
• Actual Duration (Months): 11
• Patients Per Site: 5.8
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The purpose of the study was to evaluate whether LIK066 can be developed for the treatment of polycystic ovary syndrome (PCOS) in overweight and obese women.

Condition or Disease	Intervention/Treatment	Phase
Polycystic Ovary Syndrome	Drug: LIK066; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: A Randomized, Subject- and Investigator-blinded, Placebo-controlled Pharmacodynamic Study of Oral LIK066 in Overweight and Obese Women With Polycystic Ovary Syndrome
• Actual Study Start Date: Jul 24, 2017
• Actual Primary Completion Date: Jun 25, 2018
• Actual Study Completion Date: Jun 25, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: LIK066 LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Drug: LIK066; LIK066 tablets for oral administration
Placebo Comparator: Placebo Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Drug: Placebo; Placebo tablets matching LIK066 tablets, for oral administration

Outcome Measures

Primary Outcome Measures

1. Change in Average Morning Fasting Free Testosterone Blood Concentrations From Baseline [Baseline, Day 15]

Secondary Outcome Measures

1. Change From Baseline in Luteinizing Hormone (LH) at Day 15 [Baseline, Day 15]

2. Change From Baseline in Follicle Stimulating Hormone (FSH) at Day 15 [Baseline, Day 15]

3. Change From Baseline in Sex Hormone Binding Globulin (SHBG) at Day 15 [Baseline, Day 15]

4. Change From Baseline in Androstenedione at Day 15 [Baseline, Day 15]

5. Change From Baseline in Dehydroepiandrostenedione (DHEA) at Day 15 [Baseline, Day 15]

6. Change From Baseline in Dehydroepiandrostenedione Sulfate (DHEAS) at Day 15 [Baseline, Day 15]

7. Change From Baseline in Total Testosterone, at Day 15 [Baseline, Day 15]

8. Change From Baseline in Free Androgen Index (FAI), at Day 15 [Baseline, Day 15]

   Free Androgen Index (FAI) is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by 100. FAI has no units.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 40 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Key Inclusion Criteria:

• PCOS (diagnosed as clinical or biochemical hyperandrogenism, amenorrhea or oligomenorrhea and exclusion of other causes of hyperandrogenism.

• Overweight/obese female subjects with BMI of 28 - 45 kg/m^2, inclusive, and stable weight +/- 3 kg over previous 3 months

• Subjects must use non-hormonal methods of contraception during the study.

Key Exclusion Criteria:

• Subjects with exogenous causes of hirsutism

• Menstruation in the 30 days prior to screening or treatment

• Pregnant or nursing (lactating) women

• Use of prohibited medications

• Preexisting medical condition which may significantly alter the absorption, metabolism, or excretion of the study drug, or which may jeopardize the subject in case of participation in the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Novartis Investigative Site	Springfield	Missouri	United States	65802
2	Novartis Investigative Site	Philadelphia	Pennsylvania	United States	19104
3	Novartis Investigative Site	Berlin		Germany	10117
4	Novartis Investigative Site	Essen		Germany	45147
5	Novartis Investigative Site	Freiburg		Germany	79106

Sponsors and Collaborators

• Novartis Pharmaceuticals

Investigators

• Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study Documents (Full-Text)

• Statistical Analysis Plan - Oct 3, 2017
• Study Protocol - Sep 20, 2017

More Information

Additional Information:

• A Plain Language Trial Summary is available on novartisclinicatrials.com

Publications

None provided.

• Responsible Party: Novartis Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT03152591
• Other Study ID Numbers: CLIK066X2205; 2017-001373-16
• First Posted: May 15, 2017
• Last Update Posted: Jan 5, 2021
• Last Verified: Sep 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Novartis Pharmaceuticals: Polycystic ovary syndrome; PCOS; hyperandrogenism; insulin resistance; overweight; obesity
• Additional relevant MeSH terms: Polycystic Ovary Syndrome; Syndrome; Overweight; Licogliflozin

Study Results

Participant Flow

Recruitment Details	This study was conducted in 5 centers in 2 countries: Germany (3), and USA (2).
Pre-assignment Detail	Participants were randomized in the ratio of 1:1 to receive either LIK066 50 mg tid or placebo for 14 days and morning dose on Day 15.

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Period Title: Overall Study
STARTED	15	14
Pharmacokinetic (PK) Analysis Set	14	0
Pharmacodynamic (PD) Analysis Set	15	14
COMPLETED	15	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	LIK066	Placebo	Total
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Total of all reporting groups
Overall Participants	15	14	29
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	26.1 (4.76)	29.1 (5.66)	27.6 (5.34)
Sex/Gender, Customized (Number) [Number]
Female	15 100%	14 100%	29 100%
Race/Ethnicity, Customized (Number) [Number]
White	15 100%	14 100%	29 100%
Average fasting total testosterone (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	1.98 (0.841)	2.07 (0.608)	2.02 (0.724)
Average fasting free testosterone (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	0.037 (0.0163)	0.032 (0.0086)	0.034 (0.0132)
Sex hormone binding globulin (SHBG) (nmol/L) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [nmol/L]	18.3 (7.72)	24.6 (10.51)	21.4 (9.58)
Free androgen Index (ratio) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ratio]	12.4 (6.65)	9.0 (2.77)	10.7 (5.27)

Outcome Measures

1. Primary Outcome

Title	Change in Average Morning Fasting Free Testosterone Blood Concentrations From Baseline
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [nmol/L]	0.91	1.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.353
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	0.88
	Confidence Interval	(2-Sided) 90%; 0.70 to 1.11
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline in average fasting free testosterone was analyzed using an analysis of covariance model which included treatment as a categorical factor, baseline body weight and log transformed baseline average fasting free testosterone as a covariate.

2. Secondary Outcome

Title	Change From Baseline in Luteinizing Hormone (LH) at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [U/L]	1.37	1.10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.218
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	1.25
	Confidence Interval	(2-Sided) 90%; 0.92 to 1.68
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

3. Secondary Outcome

Title	Change From Baseline in Follicle Stimulating Hormone (FSH) at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [U/L]	1.13	0.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.249
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	1.27
	Confidence Interval	(2-Sided) 90%; 0.90 to 1.78
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

4. Secondary Outcome

Title	Change From Baseline in Sex Hormone Binding Globulin (SHBG) at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [nmol/L]	1.06	0.93

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.173
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	1.15
	Confidence Interval	(2-Sided) 90%; 0.97 to 1.36
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < LLOQ and values > ULOQ are imputed as LLOQ/2 and ULOQ respectively.
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

5. Secondary Outcome

Title	Change From Baseline in Androstenedione at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [nmol/L]	0.85	1.03

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.089
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 90%; 0.68 to 0.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < LLOQ and values > ULOQ are imputed as LLOQ/2 and ULOQ respectively
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

6. Secondary Outcome

Title	Change From Baseline in Dehydroepiandrostenedione (DHEA) at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [nmol/L]	0.75	1.09

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.109
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ration LIK066/Placebo
	Estimated Value	0.69
	Confidence Interval	(2-Sided) 90%; 0.48 to 1.01
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < LLOQ and values > ULOQ are imputed as LLOQ/2 and ULOQ respectively.
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

7. Secondary Outcome

Title	Change From Baseline in Dehydroepiandrostenedione Sulfate (DHEAS) at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [umol/L]	0.84	1.10

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ration LIK066/Placebo
	Estimated Value	0.76
	Confidence Interval	(2-Sided) 90%; 0.65 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < LLOQ and values > ULOQ are imputed as LLOQ/2 and ULOQ respectively.
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

8. Secondary Outcome

Title	Change From Baseline in Total Testosterone, at Day 15
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [nmol/L]	0.95	1.04

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.340
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	0.91
	Confidence Interval	(2-Sided) 90%; 0.77 to 1.07
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

9. Secondary Outcome

Title	Change From Baseline in Free Androgen Index (FAI), at Day 15
Description	Free Androgen Index (FAI) is a ratio used to determine abnormal androgen status in humans. The ratio is the total testosterone level divided by the sex hormone binding globulin (SHBG) level, and then multiplying by 100. FAI has no units.
Time Frame	Baseline, Day 15

Outcome Measure Data

Analysis Population Description

Pharmacodynamic (PD) analysis set

Arm/Group Title	LIK066	Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test	Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
Measure Participants	15	14
Geometric Mean (90% Confidence Interval) [Ratio]	0.85	1.07

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	LIK066, Placebo
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.204
	Comments
	Method	t-test, 2 sided
	Comments	Two-sided test at the 0.1 significance level
Method of Estimation	Estimation Parameter	Ratio LIK066/Placebo
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 90%; 0.58 to 1.08
	Parameter Dispersion	Type: Value:
	Estimation Comments	Values < LLOQ and values > ULOQ are imputed as LLOQ/2 and ULOQ respectively.
Other Statistical Analysis		Log transformed ratio of Day 15 to baseline was analyzed using an analysis of covariance model which will include treatment as a categorical factor and log transformed baseline as a covariate.

Adverse Events

Time Frame	Adverse Events were collected for the maximum duration of participants' treatment exposure plus any follow up period, approximately 2 months.
Arm/Group Title	LIK066		Placebo
Arm/Group Description	LIK066 tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test		Placebo tablets received three times daily; before breakfast, lunch and dinner for 14 days and once on day 15 morning before meal test
All Cause Mortality
	LIK066		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)
Serious Adverse Events
	LIK066		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/14 (0%)
Other (Not Including Serious) Adverse Events
	LIK066		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	15/15 (100%)		10/14 (71.4%)
Gastrointestinal disorders
ABDOMINAL DISTENSION	2/15 (13.3%)		0/14 (0%)
ABDOMINAL PAIN	2/15 (13.3%)		0/14 (0%)
ABDOMINAL PAIN UPPER	1/15 (6.7%)		0/14 (0%)
DIARRHOEA	15/15 (100%)		3/14 (21.4%)
DYSPEPSIA	1/15 (6.7%)		0/14 (0%)
FLATULENCE	6/15 (40%)		0/14 (0%)
GASTROINTESTINAL TRACT IRRITATION	0/15 (0%)		1/14 (7.1%)
NAUSEA	5/15 (33.3%)		2/14 (14.3%)
VOMITING	0/15 (0%)		1/14 (7.1%)
General disorders
THIRST	4/15 (26.7%)		1/14 (7.1%)
Infections and infestations
NASOPHARYNGITIS	2/15 (13.3%)		1/14 (7.1%)
RHINITIS	1/15 (6.7%)		0/14 (0%)
VAGINAL INFECTION	1/15 (6.7%)		0/14 (0%)
VULVOVAGINAL MYCOTIC INFECTION	1/15 (6.7%)		0/14 (0%)
Investigations
MENSTRUATION NORMAL	4/15 (26.7%)		2/14 (14.3%)
Metabolism and nutrition disorders
DECREASED APPETITE	1/15 (6.7%)		0/14 (0%)
Musculoskeletal and connective tissue disorders
MUSCULOSKELETAL DISCOMFORT	0/15 (0%)		1/14 (7.1%)
Nervous system disorders
HEADACHE	4/15 (26.7%)		1/14 (7.1%)
MIGRAINE	0/15 (0%)		1/14 (7.1%)
Psychiatric disorders
INSOMNIA	1/15 (6.7%)		0/14 (0%)
MOOD ALTERED	1/15 (6.7%)		0/14 (0%)
Renal and urinary disorders
POLYURIA	0/15 (0%)		1/14 (7.1%)
Reproductive system and breast disorders
HYPOMENORRHOEA	2/15 (13.3%)		1/14 (7.1%)
MENSTRUAL DISORDER	0/15 (0%)		1/14 (7.1%)
Respiratory, thoracic and mediastinal disorders
DRY THROAT	0/15 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
RASH	1/15 (6.7%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The terms and conditions of Novartis' agreements with its investigators may vary. However, Novartis does not prohibit any investigator from publishing. Any publications from a single-site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.