Long-term Study of Alogliptin as an Add-on to Rapid-Acting Insulin Secretagogues in Type 2 Diabetes

• Sponsor: Takeda (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01456130
• Collaborator: (none)
• Enrollment: 67
• Locations: 14
• Arm: 1
• Duration (Months): 16
• Patients Per Site: 4.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to evaluate the safety and efficacy of alogliptin as an add-on to a rapid-acting insulin secretagogue (medicine that stimulates insulin release) in type 2 diabetic patients with inadequate blood glucose control despite treatment with a rapid-acting insulin secretagogue as well as diet and exercise therapies.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus	Drug: Alogliptin; Drug: Rapid-acting insulin secretagogue	Phase 3

Detailed Description

One alogliptin 25 mg tablet was orally administered once daily before breakfast for up to 52 weeks.

The dose of alogliptin was adjusted according to the severity of the participant's renal dysfunction based on serum creatinine (SCr) levels. Participants with moderate renal dysfunction (SCr, >1.4 - ≤2.4 mg/dL for men and >1.2 - ≤ 2.0 mg/dL for women) received alogliptin 12.5 mg tablets.

Study Design

• Study Type: Interventional
• Actual Enrollment: 67 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: A Long-Term, Open-Label Study to Investigate the Long-Term Safety of SYR-322 When Used in Combination With Rapid-Acting Insulin Secretagogues in Subjects With Type 2 Diabetes in Japan
• Study Start Date: Nov 1, 2011
• Actual Primary Completion Date: Mar 1, 2013
• Actual Study Completion Date: Mar 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Alogliptin Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.	Drug: Alogliptin; Alogliptin tablets; Other Names: SYR-322 Nesina® ; Drug: Rapid-acting insulin secretagogue; Either of the following commercially available rapid-acting insulin secretagogues as prescribed by the Investigator: (i) Nateglinide: Dose: 30 mg tablet or 90 mg tablet (ii) Mitiglinide calcium hydrate: Dose: 5 mg tablet or 10 mg tablet

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Treatment Emergent Adverse Events (TEAEs) [52 Weeks]

   An TEAE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious TEAE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above.

Secondary Outcome Measures

1. Change From Baseline in Glycosylated Hemoglobin (HbA1c) [Baseline and Week 52]

   The change in the value of glycosylated hemoglobin collected at Week 52 or at the final visit relative to Baseline.

2. Percentage of Participants With a Clinical Response [Week 52]

   Clinical response is defined as an HbA1c level less than 5.8% or less than 6.5% at Week 52 or at the final visit.

3. Change From Baseline in Fasting Glucose [Baseline and Week 52]

   The change in the value of fasting glucose collected at Week 52 or the final visit relative to Baseline.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 20 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Diagnosed with type 2 diabetes mellitus.

2. Had an HbA1c of ≥ 6.5% and < 10.0% at the start of the observation period (Week -2).

3. Had been receiving specific diet and exercise (if applicable) therapies since at least 10 weeks prior to the start of the observation period (Week -2).

4. Had been receiving basic diabetes treatment with a rapid-acting insulin secretagogue (nateglinide or mitiglinide calcium hydrate) alone using a stable dosage regimen since at least 10 weeks prior to the start of the observation period (Week -2).

5. Was suitable for combination therapy of either of the above rapid-acting insulin secretagogues (nateglinide or mitiglinide calcium hydrate) and another antidiabetic drug at the start of the observation period (Week -2) in the investigator's or subinvestigator's opinion.

6. Participants complicated by hypertension had stable blood pressure control and needed neither dose adjustment of the ongoing antihypertensive (including discontinuation and interruption) nor additional use of another antihypertensive throughout the duration of the study in the investigator's or subinvestigator's opinion.

7. Male or female and aged 20 years or older at the time of signing of informed consent.

8. If female, and of child-bearing potential and sexually active with a nonsterilized male partner agreed to use adequate contraception routinely from signing of informed consent throughout the duration of the study.

9. Visited the study site on an outpatient basis during the observation period.

10. Was capable of understanding and complying with protocol requirements in the investigator's or subinvestigator's opinion.

11. Signed and dated the informed consent documents prior to the start of any study procedures.

Exclusion Criteria:

1. Severe renal dysfunction or end-stage renal disease [e.g., a serum creatinine (SCr) level of >2.4 mg/dL (men) or >2.0 mg/dL (women) at the start of the observation period (Week -2)].

2. Obvious clinical manifestations of hepatic impairment [e.g., an aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value of ≥ 2.5 times the upper limit of normal at the start of the observation period (Week -2)].

3. Any serious cardiac disease, serious cerebrovascular disorder, or serious pancreatic or hematological disease (e.g., requiring hospitalization for treatment).

4. Systolic blood pressure of ≥ 180 mmHg or diastolic blood pressure of ≥ 110 mmHg during the observation period.

5. A condition requiring insulin for blood glucose control (e.g., a patient with severe ketosis, diabetic coma or precoma, type 1 diabetes mellitus, severe infection, a pre- or post-operative condition, or serious trauma).

6. Malignant tumor.

7. History of hypersensitivity or allergies to dipeptidyl-peptidase-4 (DPP-4) inhibitors.

8. A habitual drinker whose daily alcohol consumption was >100 mL on average.

9. A history of drug abuse (defined as any illicit drug use) or alcohol abuse.

10. Required to take excluded medications during the duration of the study.

11. Previously received SYR-322 or Nesina® Tablets in a clinical study or as a therapeutic drug.

12. Received any investigational product (including investigational products for postmarketing clinical studies) within 12 weeks prior to the start of the observation period.

13. Had participated in another clinical study at signing of informed consent.

14. If female, was pregnant or lactating, or intended to become pregnant between signing of informed consent and 1 month after the end of the study; or intended to donate ova during such time period.

15. A study site employee, an immediate family member of a study site employee or in a dependent relationship with a study site employee who was involved in the conduct of this study (e.g., spouse, parent, child, sibling), or might consent under duress.

16. Changed the dosing regimen of the ongoing rapid-acting insulin secretagogue during the observation period.

17. History of hypersensitivity or allergies to rapid-acting insulin secretagogues.

18. Any condition for which Nesina® Tablets, nateglinide, or mitiglinide calcium hydrate was contraindicated as defined in their package inserts.

19. Otherwise ineligible for participation in the study in the investigator's or subinvestigator's opinion.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Nagoya-shi	Aichi	Japan
2		Fukuoka-shi	Fukuoka	Japan
3		Kurume-shi	Fukuoka	Japan
4		Sapporo-shi	Hokkaido	Japan
5		Kobe-shi	Hyogo	Japan
6		Kagoshima-shi	Kagoshima	Japan
7		Kumamoto-shi	Kumamoto	Japan
8		Osaki-shi	Miyagi	Japan
9		Minou-shi	Osaka	Japan
10		Osaka-shi	Osaka	Japan
11		Kamio-shi	Saitama	Japan
12		Koshigaya-shi	Saitama	Japan
13		Adachi-ku	Tokyo	Japan
14		Chuo-ku	Tokyo	Japan

Sponsors and Collaborators

• Takeda

Investigators

• Study Director: Medical Director, Clinical Science, Takeda

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Takeda
• ClinicalTrials.gov Identifier: NCT01456130
• Other Study ID Numbers: SYR-322/OCT-901; U1111-1124-8848; JapicCTI-111643
• First Posted: Oct 20, 2011
• Last Update Posted: Apr 21, 2014
• Last Verified: Mar 1, 2014

• Additional relevant MeSH terms: Diabetes Mellitus; Alogliptin; Insulin, Short-Acting; Secretagogues

Study Results

Participant Flow

Recruitment Details	Participants took part in the study at 14 investigative sites in Japan from 10 November 2011 to 16 March 2013.
Pre-assignment Detail	Patients with type 2 diabetes with inadequate blood glucose control despite treatment with a rapid-acting insulin secretagogue as well as diet and exercise therapies were enrolled in a single treatment group.

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Period Title: Overall Study
STARTED	67
COMPLETED	57
NOT COMPLETED	10

Baseline Characteristics

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Overall Participants	67
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61.6 (10.52)
Age, Customized (participants) [Number]
< 65 years	37 55.2%
≥ 65 years	30 44.8%
Sex: Female, Male (Count of Participants)
Female	26 38.8%
Male	41 61.2%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	66.64 (14.409)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	161.7 (10.22)
Body Mass Index (BMI) (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	25.38 (4.347)
Duration of Diabetes (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	7.44 (5.872)
Glycosylated Hemoglobin (HbA1c) (percent glycosylated hemoglobin) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [percent glycosylated hemoglobin]	7.63 (0.957)
Baseline hemoglobin A1c (HbA1c) categories (participants) [Number]
< 6.5 %	3 4.5%
≥ 6.5 and < 7.0%	17 25.4%
≥ 7.0 and < 8.0%	25 37.3%
≥ 8.0%	22 32.8%
Fasting blood glucose (mg/dL) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [mg/dL]	182.1 (45.07)
Fasting blood glucose categories (participants) [Number]
< 130 mg/dL	6 9%
≥ 130 to < 160 mg/dL	17 25.4%
≥ 160 mg/dL	44 65.7%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Treatment Emergent Adverse Events (TEAEs)
Description	An TEAE is any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have a causal relationship with this treatment. A serious TEAE is defined as any untoward medical occurrence that resulted in death, was life threatening, required or prolonged inpatient hospitalization, resulted in persistent or significant disability or incapacity, led to a congenital anomaly/birth defect or was an important medical event that may have required intervention to prevent any of items above.
Time Frame	52 Weeks

Outcome Measure Data

Analysis Population Description

Safety analysis set - All participants who received at least one dose of the investigational product (alogliptin) and a rapid-acting insulin secretagogue.

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Measure Participants	67
Any adverse event	57 85.1%
Adverse event leading to discontinuation	5 7.5%
Serious adverse event (SAE)	6 9%
SAE leading to discontinuation	0 0%
Death	0 0%

2. Secondary Outcome

Title	Change From Baseline in Glycosylated Hemoglobin (HbA1c)
Description	The change in the value of glycosylated hemoglobin collected at Week 52 or at the final visit relative to Baseline.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set: All randomized participants who received at least one dose of double-blind study medication.

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Measure Participants	67
Mean (95% Confidence Interval) [percentage of glycosylated hemoglobin]	-0.46

3. Secondary Outcome

Title	Percentage of Participants With a Clinical Response
Description	Clinical response is defined as an HbA1c level less than 5.8% or less than 6.5% at Week 52 or at the final visit.
Time Frame	Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Measure Participants	67
HbA1c of < 5.8%	4.5 6.7%
HbA1c of < 6.5%	28.4 42.4%

4. Secondary Outcome

Title	Change From Baseline in Fasting Glucose
Description	The change in the value of fasting glucose collected at Week 52 or the final visit relative to Baseline.
Time Frame	Baseline and Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set.

Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
Measure Participants	67
Mean (95% Confidence Interval) [mg/dL]	-10.5

Adverse Events

Time Frame	52 weeks
Adverse Event Reporting Description	At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
Arm/Group Title	Alogliptin
Arm/Group Description	Alogliptin 25 mg (or 12.5 mg for participants with moderate renal dysfunction) tablets, orally once daily and a rapid-acting insulin secretagogue as prescribed by the Investigator for up to 52 weeks.
All Cause Mortality
	Alogliptin
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Alogliptin
	Affected / at Risk (%)	# Events
Total	6/67 (9%)
Cardiac disorders
Myocardial infarction	1/67 (1.5%)
Gastrointestinal disorders
Duodenal ulcer	1/67 (1.5%)
Inguinal hernia	1/67 (1.5%)
Infections and infestations
Bronchiolitis	1/67 (1.5%)
Musculoskeletal and connective tissue disorders
Back pain	1/67 (1.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acute lymphocytic leukaemia	1/67 (1.5%)
Other (Not Including Serious) Adverse Events
	Alogliptin
	Affected / at Risk (%)	# Events
Total	57/67 (85.1%)
Blood and lymphatic system disorders
Anaemia	2/67 (3%)
Eye disorders
Asthenopia	3/67 (4.5%)
Cataract	2/67 (3%)
Conjunctivitis allergic	2/67 (3%)
Diabetic retinopathy	2/67 (3%)
Gastrointestinal disorders
Constipation	5/67 (7.5%)
Dental caries	4/67 (6%)
Gastrooesophageal reflux disease	4/67 (6%)
Abdominal pain upper	2/67 (3%)
General disorders
Chest pain	2/67 (3%)
Malaise	2/67 (3%)
Immune system disorders
Seasonal allergy	3/67 (4.5%)
Infections and infestations
Nasopharyngitis	24/67 (35.8%)
Bronchitis	4/67 (6%)
Cellulitis	2/67 (3%)
Gastroenteritis	2/67 (3%)
Gingivitis	2/67 (3%)
Influenza	2/67 (3%)
Oral herpes	2/67 (3%)
Periodontitis	2/67 (3%)
Injury, poisoning and procedural complications
Arthropod sting	2/67 (3%)
Investigations
Gamma-glutamyltransferase increased	2/67 (3%)
Metabolism and nutrition disorders
Hyperuricaemia	2/67 (3%)
Musculoskeletal and connective tissue disorders
Arthralgia	5/67 (7.5%)
Back pain	4/67 (6%)
Nervous system disorders
Headache	3/67 (4.5%)
Psychiatric disorders
Insomnia	2/67 (3%)
Sleep disorder	2/67 (3%)
Renal and urinary disorders
Diabetic nephropathy	4/67 (6%)
Respiratory, thoracic and mediastinal disorders
Upper respiratory tract inflammation	8/67 (11.9%)
Skin and subcutaneous tissue disorders
Eczema	2/67 (3%)
Rash	2/67 (3%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.