Trial Outcomes & Findings for Insulin Glargine "All to Target" Trial (NCT NCT00384085)

Last Updated: 2011-05-06

Results Overview

Responders defined as patients who achieved an HbA1c value \<7.0% versus nonresponders. Patients who did not achieve an HbA1c value \<7.0% and patients with a missing HbA1c value at Week 60 were considered to be nonresponders.

Recruitment status

COMPLETED

Study phase

PHASE4

Target enrollment

588 participants

Primary outcome timeframe

At week 60

Results posted on

2011-05-06

Participant Flow

A total of 123 study sites were activated in the United States; 99 sites enrolled and randomized 588 patients from May 2006 to March 2010. 582 patients out of 588 patients were treated. Three sites (which included 26 patients) were found to be non Good Clinical Practices (GCP) compliant.

Patient were considered enrolled after informed consent were obtained, and randomized after completion of the 4-week run-in phase and assessment of the randomization criteria.

Participant milestones

Participant milestones
Measure	Lantus/Apidra-3 Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Lantus/Apidra-1 Insulin glargine (Lantus) plus up to 1 injection of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Overall Study STARTED	195	196	197
Overall Study Intent-To-Treat (ITT)	195	196	197
Overall Study Treated (Safety Population)	194	194	194
Overall Study Intent-To-Treat (Excluding nonGCP Sites)	187	186	189
Overall Study COMPLETED	156	150	141
Overall Study NOT COMPLETED	39	46	56

Reasons for withdrawal

Reasons for withdrawal
Measure	Lantus/Apidra-3 Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Lantus/Apidra-1 Insulin glargine (Lantus) plus up to 1 injection of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Overall Study Adverse Event	5	5	4
Overall Study Lack of Efficacy	0	3	2
Overall Study No longer Requires Study Treatment	1	0	1
Overall Study Protocol Violation	2	2	2
Overall Study Lost to Follow-up	9	9	10
Overall Study Progressive Disease	0	1	0
Overall Study Withdrawal by Subject	14	19	29
Overall Study Patient non-compliant	4	4	5
Overall Study Physician Decision	1	0	0
Overall Study Loss of site personnel	1	0	1
Overall Study Sponsor decision	1	2	1
Overall Study Patient moved	1	0	1
Overall Study Patient required surgery	0	1	0

Baseline Characteristics

Insulin Glargine "All to Target" Trial

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Lantus/Apidra-3 n=195 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Lantus/Apidra-1 n=196 Participants Insulin glargine (Lantus) plus up to 1 injection of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=197 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Total n=588 Participants Total of all reporting groups
Age Continuous	54.9 years STANDARD_DEVIATION 10.54 • n=5 Participants	53.7 years STANDARD_DEVIATION 9.11 • n=7 Participants	53.7 years STANDARD_DEVIATION 10.65 • n=5 Participants	54.1 years STANDARD_DEVIATION 10.12 • n=4 Participants
Sex: Female, Male Female	78 Participants n=5 Participants	88 Participants n=7 Participants	86 Participants n=5 Participants	252 Participants n=4 Participants
Sex: Female, Male Male	117 Participants n=5 Participants	108 Participants n=7 Participants	111 Participants n=5 Participants	336 Participants n=4 Participants
Region of Enrollment United States	195 participants n=5 Participants	196 participants n=7 Participants	197 participants n=5 Participants	588 participants n=4 Participants
Weight	95.2 kilograms (kg) STANDARD_DEVIATION 19.21 • n=5 Participants	97.2 kilograms (kg) STANDARD_DEVIATION 20.88 • n=7 Participants	97.9 kilograms (kg) STANDARD_DEVIATION 20.49 • n=5 Participants	96.8 kilograms (kg) STANDARD_DEVIATION 20.21 • n=4 Participants
Body Mass Index (BMI)	32.7 Kilogram/m^2 STANDARD_DEVIATION 5.79 • n=5 Participants	33.4 Kilogram/m^2 STANDARD_DEVIATION 6.00 • n=7 Participants	33.4 Kilogram/m^2 STANDARD_DEVIATION 5.62 • n=5 Participants	33.1 Kilogram/m^2 STANDARD_DEVIATION 5.80 • n=4 Participants
Duration of diabetes at study entry	9.4 years STANDARD_DEVIATION 6.80 • n=5 Participants	9.1 years STANDARD_DEVIATION 5.70 • n=7 Participants	9.5 years STANDARD_DEVIATION 5.87 • n=5 Participants	9.3 years STANDARD_DEVIATION 6.13 • n=4 Participants
Age at onset of diabetes	46.0 years STANDARD_DEVIATION 10.74 • n=5 Participants	45.1 years STANDARD_DEVIATION 9.36 • n=7 Participants	44.8 years STANDARD_DEVIATION 10.01 • n=5 Participants	45.3 years STANDARD_DEVIATION 10.05 • n=4 Participants
Oral antidiabetic treatment combination at study entry sulfonylurea (SU) or meglitinide plus metformin	97 participants n=5 Participants	99 participants n=7 Participants	97 participants n=5 Participants	293 participants n=4 Participants
Oral antidiabetic treatment combination at study entry SU or meglitinide plus thiazolinedione (TZD)	9 participants n=5 Participants	9 participants n=7 Participants	10 participants n=5 Participants	28 participants n=4 Participants
Oral antidiabetic treatment combination at study entry TZD plus metformin	26 participants n=5 Participants	27 participants n=7 Participants	27 participants n=5 Participants	80 participants n=4 Participants
Oral antidiabetic treatment combination at study entry SU or meglitinide plus metformin plus TZD	63 participants n=5 Participants	61 participants n=7 Participants	63 participants n=5 Participants	187 participants n=4 Participants

PRIMARY outcome

Timeframe: At week 60

Population: Analysis was performed on Intent-To-Treat population which consisted of all patients who were randomized and for whom there was any post-baseline follow-up information. Patients from nonGCP compliant sites were excluded from this analysis. Additional analysis including those patients were completed to ensure that study results were not compromised.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=187 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=189 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) HbA1c < 7.0%	43.3 percentage of participants	38.6 percentage of participants	—
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) HbA1c ≥ 7.0%	35.3 percentage of participants	32.3 percentage of participants	—
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - Intent To Treat (ITT) Population Without Good Clinical Practices (GCP) Noncompliant Sites) Missing data	21.4 percentage of participants	29.1 percentage of participants	—

PRIMARY outcome

Timeframe: At week 60

Population: Analysis was performed on the Per Protocol (PP) population which included randomized patients who had no major protocol violation and who had HbA1c recorded for both Baseline \& Week 60. Patients from non-GCP compliant sites were, by population definition, excluded from this analysis.

Absolute Change in HbA1c from Baseline to Week 60. If the Week 60 HbA1c evaluation was missing, the patient was counted as having not completed per protocol.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=138 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=134 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population baseline HbA1c	9.30 percent HbA1c Standard Error 0.176	9.06 percent HbA1c Standard Error 0.187	—
Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)Per Protocol Population Absolute change in HbA1c from baseline	-2.30 percent HbA1c Standard Error 0.126	-1.97 percent HbA1c Standard Error 0.132	—

PRIMARY outcome

Timeframe: At week 60

Population: Analysis was performed on the Intent To Treat (ITT) population which consisted of all patients who were randomized, and for whom there was any post-baseline follow-up information. Patients from non-GCP compliant sites were included in this analysis. This analysis was performed to ensure that study results were not compromised.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=195 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=197 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) HbA1c < 7.0%	44.1 percentage of participants	38.1 percentage of participants	—
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) HbA1c ≥ 7.0%	34.4 percentage of participants	32.0 percentage of participants	—
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) < 7.0% at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30 - ITT Population With All Sites) (Sensitivity Analysis) Missing data	21.5 percentage of participants	29.9 percentage of participants	—

SECONDARY outcome

Timeframe: From baseline to week 60

Population: Analysis was performed on the modified ITT (mITT) population which consisted of all patients who were randomized, and for whom there was a baseline observation and at least 1 postbaseline (on therapy) observation for HbA1c. Patients from non-GCP compliant sites (8 from Lantus/Apidra-3 \& 7 from Novolog Mix arms) were excluded from this analysis.

Absolute Change in HbA1c from Baseline to Week 60.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=144 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=134 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Absolute Change From Baseline in Glycosylated Hemoglobin A1c (HbA1c) at Week 60 (Lantus/Apidra-3 Versus Novolog Mix 70/30)	-2.45 percent HbA1c Standard Error 0.134	-2.13 percent HbA1c Standard Error 0.142	—

SECONDARY outcome

Timeframe: At week 60

Population: Analysis was performed on the modified intent-to-treat population which consisted of all patients who were randomized \& for whom there was a baseline observation \& at least 1 postbaseline (on therapy) observation for HbA1c. Patients from non-GCP compliant sites (9 for Lantus/Apidra-1 \& 7 for Novolog Mix arms) were excluded from this analysis.

Patients who achieved an HbA1c value \<7.0% were defined as responders. Patients who did not achieve HbA1c values \<7.0% and patients with missing HbA1c values were considered nonresponders.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=180 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=185 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 (Lantus/Apidra-1 Versus Novolog Mix 70/30)	51.1 percentage of participants	39.5 percentage of participants	—

SECONDARY outcome

Timeframe: At week 60

Population: Analysis was performed on the mITT population. Patients from non-GCP compliant sites (8 from Lantus/Apidra-3, 9 from Lantus/Apidra-1 \& 7 from Novolog Mix arms) were excluded from this analysis.

Severe hypoglycemia was defined as an event with clinical symptoms that are considered to result from hypoglycemia in which the patient required assistance of another person and one of the following: the event was associated with a measured blood glucose level below 36 mg/dL or the event was associated with prompt recovery after oral carbohydrate, iv glucose, or glucagon administration. A symptomatic hypoglycemic event was defined as a hypoglycemic episode with an associated SMBG value of \<50 mg/dL with reported symptoms.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=183 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=180 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 n=185 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl HbA1c < 7.0%	23.0 percentage of participants	25.0 percentage of participants	14.1 percentage of participants
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl HbA1c ≥ 7.0%	55.7 percentage of participants	52.2 percentage of participants	58.4 percentage of participants
Percentage of Patients Achieving Glycosylated Hemoglobin A1c (HbA1c) <7.0% at Week 60 Without a Severe Hypoglycemic Event or a Symptomatic Hypoglycemic Event With an Self Monitoring Blood Glucose (SMBG) <50 mg/dl Missing data	21.3 percentage of participants	22.8 percentage of participants	27.6 percentage of participants

SECONDARY outcome

Timeframe: Week 60

Population: The analysis was performed on the exposed population (i.e. safety population) regardless of enrollment in a non-GCP compliant site.

Adjusted incidence rate of hypoglycemia: estimated percent of patients having at least 1 event of a given type of hypoglycemia. A severe Hypoglycemic Event (HE) is one where patient requires assistance. It is confirmed either by a prompt response to certain countermeasures or by a blood Glucose (BG) \<36 mg/dL during or soon after the event. A serious HE is one where the patient has loss of consciousness, coma, seizure, or convulsion. Nocturnal = events occurring between 00:00 \& 06:00 based on a 24-hour clock. An event is included if the HE start date is within the treatment period.

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=194 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=194 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 n=194 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Adjusted Incidence Rate of Hypoglycemia Self-Monitored Blood Glucose (SMBG) < 70 mg/dl	74.40 estimated percentage per patient Standard Error 3.83	74.78 estimated percentage per patient Standard Error 3.80	83.15 estimated percentage per patient Standard Error 3.11
Adjusted Incidence Rate of Hypoglycemia SMBG< 70 mg/dl with symptoms	60.14 estimated percentage per patient Standard Error 4.24	62.50 estimated percentage per patient Standard Error 4.18	71.98 estimated percentage per patient Standard Error 3.76
Adjusted Incidence Rate of Hypoglycemia SMBG< 70 mg/dl, nocturnal	46.30 estimated percentage per patient Standard Error 4.28	40.31 estimated percentage per patient Standard Error 4.18	42.53 estimated percentage per patient Standard Error 4.19
Adjusted Incidence Rate of Hypoglycemia SMBG< 70 mg/dl with symptoms, nocturnal	37.03 estimated percentage per patient Standard Error 4.10	33.55 estimated percentage per patient Standard Error 3.98	35.68 estimated percentage per patient Standard Error 4.03
Adjusted Incidence Rate of Hypoglycemia SMBG< 50 mg/dl	39.77 estimated percentage per patient Standard Error 4.27	39.55 estimated percentage per patient Standard Error 4.25	53.14 estimated percentage per patient Standard Error 4.33
Adjusted Incidence Rate of Hypoglycemia SMBG< 50 mg/dl with symptoms	31.51 estimated percentage per patient Standard Error 3.95	32.56 estimated percentage per patient Standard Error 4.00	45.92 estimated percentage per patient Standard Error 4.30
Adjusted Incidence Rate of Hypoglycemia SMBG< 50 mg/dl, nocturnal	12.05 estimated percentage per patient Standard Error 2.88	11.29 estimated percentage per patient Standard Error 2.78	12.58 estimated percentage per patient Standard Error 2.96
Adjusted Incidence Rate of Hypoglycemia SMBG< 50 mg/dl with symptoms, nocturnal	6.93 estimated percentage per patient Standard Error 2.28	7.49 estimated percentage per patient Standard Error 2.43	8.88 estimated percentage per patient Standard Error 2.76
Adjusted Incidence Rate of Hypoglycemia SMBG< 36 mg/dl	10.89 estimated percentage per patient Standard Error 2.23	8.63 estimated percentage per patient Standard Error 2.02	14.32 estimated percentage per patient Standard Error 2.52
Adjusted Incidence Rate of Hypoglycemia Severe hypoglycemias	10.10 estimated percentage per patient Standard Error 2.17	7.19 estimated percentage per patient Standard Error 1.85	8.23 estimated percentage per patient Standard Error 1.97
Adjusted Incidence Rate of Hypoglycemia Serious hypoglycemias	0.41 estimated percentage per patient Standard Error 0.43	0.00 estimated percentage per patient Standard Error 0.00	2.29 estimated percentage per patient Standard Error 1.12

SECONDARY outcome

Timeframe: Week 60

Population: The analysis was performed on the exposed population (i.e. safety population) regardless of enrollment in a non-GCP compliant site.

Adjusted Hypoglycemic event rate: Total # of events for a given type of hypoglycemia divided by the total exposure to study drug (patient-years). Rates are estimated from a general linear model adjusted for baseline BMI and oral agent combination of antidiabetic medications on which the patient entered the study. An event is included if the hypoglycemic event start date is within the treatment period (i.e., from the Randomization date to \& including 1 day after the date of last dose of study drug).

Outcome measures

Outcome measures
Measure	Lantus/Apidra-3 n=194 Participants Insulin glargine (Lantus) plus up to 3 injections of insulin glulisine (Apidra) added to oral agents.	Novolog Mix 70/30 n=194 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.	Novolog Mix 70/30 n=194 Participants Premixed insulin (Novolog® Mix 70/30) added to oral agents.
Adjusted Hypoglycemic Event Rates (Event/Patient-year) Self-Monitored Blood Glucose (SMBG) < 70 mg/dl	14.50 event per patient year Standard Error 1.72	12.85 event per patient year Standard Error 1.50	20.42 event per patient year Standard Error 2.38
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 70 mg/dl with symptoms	7.23 event per patient year Standard Error 0.99	7.11 event per patient year Standard Error 0.99	12.23 event per patient year Standard Error 1.68
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 70 mg/dl, nocturnal	1.90 event per patient year Standard Error 0.32	1.84 event per patient year Standard Error 0.31	1.68 event per patient year Standard Error 0.29
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 70 mg/dl with symptoms, nocturnal	1.16 event per patient year Standard Error 0.21	1.10 event per patient year Standard Error 0.21	1.16 event per patient year Standard Error 0.23
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 50 mg/dl	1.38 event per patient year Standard Error 0.21	1.17 event per patient year Standard Error 0.19	2.42 event per patient year Standard Error 0.36
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 50 mg/dl with symptoms	0.89 event per patient year Standard Error 0.15	0.83 event per patient year Standard Error 0.15	1.91 event per patient year Standard Error 0.31
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 50 mg/dl, nocturnal	0.20 event per patient year Standard Error 0.06	0.18 event per patient year Standard Error 0.06	0.27 event per patient year Standard Error 0.09
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 50 mg/dl with symptoms, nocturnal	0.10 event per patient year Standard Error 0.04	0.09 event per patient year Standard Error 0.04	0.18 event per patient year Standard Error 0.07
Adjusted Hypoglycemic Event Rates (Event/Patient-year) SMBG< 36 mg/dl	0.15 event per patient year Standard Error 0.03	0.10 event per patient year Standard Error 0.03	0.23 event per patient year Standard Error 0.05
Adjusted Hypoglycemic Event Rates (Event/Patient-year) Severe hypoglycemias	0.17 event per patient year Standard Error 0.05	0.10 event per patient year Standard Error 0.03	0.17 event per patient year Standard Error 0.05
Adjusted Hypoglycemic Event Rates (Event/Patient-year) Serious hypoglycemias	NA event per patient year Standard Error NA Model did not fit data adequately to produce reliable results	NA event per patient year Standard Error NA Model did not fit data adequately to produce reliable results	NA event per patient year Standard Error NA Model did not fit data adequately to produce reliable results

Adverse Events

Lantus/Apidra-3

Serious events: 22 serious events

Other events: 140 other events

Deaths: 0 deaths

Lantus/Apidra-1

Serious events: 23 serious events

Other events: 150 other events

Deaths: 0 deaths

Novolog Mix 70/30

Serious events: 21 serious events

Other events: 152 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

sanofi-aventis

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Publication restrictions are in place

Restriction type: OTHER