Lancet Diabetes 3625 SUSTAIN 4 supplementary information ...Trial-related activities are any...

Supplementary appendixThis appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors.

Supplement to: Aroda VR, Bain SC, Cariou B, et al. Efficacy and safety of once-weekly semaglutide versus once-daily insulin glargine as add-on to metformin (with or without sulfonylureas) in insulin-naive patients with type 2 diabetes (SUSTAIN 4): a randomised, open-label, parallel-group, multicentre, multinational, phase 3a trial. Lancet Diabetes Endocrinol 2017; published online March 23. http://dx.doi.org/10.1016/S2213-8587(17)30085-2.

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Supplementary Information

Supplementary Material 1. Full eligibility criteria.

a) Inclusion criteria

For an eligible subject, all inclusion criteria must be answered "yes".

1. Informed consent obtained before any trial-related activities. Trial-related activities are any procedures that are carried out as part of the trial, including activities to determine suitability for the trial.

2. Male or female, age ≥18 years at the time of signing informed consent. 3. Insulin-naïve subjects diagnosed with type 2 diabetes and on stable diabetes treatment with metformin or

metformin and SU (metformin ≥1500 mg or maximum tolerated dose and SU ≥ half of maximum allowed dose according to national label) for at least 90 days before screening. Stable is defined as unchanged medication and unchanged dose.

4. HbA1c 7·0–10·0% (53–86 mmol/mol) both inclusive.

b) Exclusion criteria

For an eligible subject, all exclusion criteria must be answered "no".

1. Known or suspected hypersensitivity to trial product(s) or related products. 2. Previous participation in this trial. Participation is defined as signed informed consent. 3. Female who is pregnant, breast-feeding or intends to become pregnant or of childbearing potential not using

adequate contraceptive method (adequate contraceptive measures as required by local regulation or practice) throughout the trial including the 5 week follow-up period. Argentina: Barrier methods (condom or diaphragm) with spermicide; contraceptive pills or intrauterine devices (IUD). Birth control methods will be reimbursed by sponsor. Croatia: In women younger than 50 years contraceptives should be used 2 years after the last menstrual period. In women younger than 50 years postmenopausal state can be confirmed, apart from above mentioned amenorrhea lasting >2 years, also as amenorrhea lasting at least 1 year with two separate measurements of FSH values ≥40 mIU, separated by 1 month at least. Germany: Adequate contraceptive measures are implants, injectables, combined oral contraceptives, hormonal intrauterine device, sexual abstinence or vasectomised partner. United Kingdom: Adequate contraceptive measures are defined as established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device or intrauterine system, barrier methods of contraception (condom or occlusive cap with spermicidal foam/gel/film/cream/suppository), male sterilisation (where partner is sole partner of subject), or true abstinence (when in line with preferred and usual lifestyle).

4. Receipt of any investigational medicinal product within 90 days before screening. 5. Any disorder which, in the opinion of the investigator, might jeopardise subject’s safety or compliance with the

protocol. 6. Treatment with any glucose-lowering agent(s) other than stated in the inclusion criteria in a period of 90 days

before screening. An exception is short-term treatment (≤7 days in total) with insulin in connection with intercurrent illness.

7. Experienced >3 episodes of severe hypoglycaemia within 6 months prior to screening, and/or hypoglycaemia unawareness.

8. History of chronic or idiopathic acute pancreatitis. 9. Screening calcitonin value ≥50 ng/L. 10. Personal or family history of medullary thyroid carcinoma (MTC) or multiple endocrine neoplasia syndrome 2

(MEN2). 11. Severe renal impairment defined as eGFR <30 mL/min/1·73 m2 per MDRD formula (4 variable version)1,2 12. Acute coronary or cerebrovascular event within 90 days before randomisation. 13. Heart failure, New York Heart Association Class IV. 14. Known proliferative retinopathy or maculopathy requiring acute treatment according to the opinion of the

investigator.

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15. Diagnosis of malignant neoplasm in the previous 5 years (except basal cell skin cancer or squamous cell skin cancer).

16. Mental inability, unwillingness or language barrier precluding adequate understanding of or compliance with trial procedures.

Supplementary Material 2. Insulin dose titration instructions to investigators.

• Starting dose: 10 units insulin glargine • Insulin dose was titrated by the investigator based on the lowest value of the subject’s fasting 1-point profile

SMPG levels 3 days prior to visits and phone contacts

Increase of insulin glargine

Lowest pre-breakfast PG Adjustment of insulin glargine

mmol/L mg/dL

≥4·0 – <5·5 ≥71 – <100 No adjustment

≥5·5 – <6·7 ≥100 – <120 +0–2 (at the discretion of the investigator)

≥6·7 – <7·8 ≥120 – <140 +2

≥7·8 – <10·0 ≥140 – <180 +4

≥10·0 ≥180 +6–8 (at the discretion of the investigator)

Decrease of insulin glargine

Lowest pre-breakfast PG Adjustment of insulin glargine

mmol/L mg/dL

<3·1 <56 –4 (for doses >45 IU, suggest dose reduction of 10%)

≥3·1 – <4·0 ≥56 – <71 –2 (for doses >45 IU, suggest dose reduction of 5%)

Supplementary Material 3. Events adjudicated by event adjudication committee (EAC).

The following adverse events were adjudicated in this trial by the EAC:

• Fatal events (if not covered by another medical event of special interest [MESI]) • Acute coronary syndrome • Cerebrovascular event (stroke or transient ischaemic attack) • Coronary revascularisation procedure • Heart failure requiring hospital admission • Neoplasm (excluding thyroid neoplasm) • Thyroid disease (including thyroid neoplasm or resulting in thyroidectomy) • Pancreatitis or clinical symptoms leading to suspicion of pancreatitis

1National Institute for Health and Clinical Excellence. Chronic kidney disease. Early identification and management of chronic kidney disease in adults in primary and secondary care. NICE guideline 73. NICE, London 2008. 2National Kidney Foundation. "K/DOQI clinical practice guidelines for chronic kidney disease". 2002.

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Supplementary Material 4. Prespecified hierarchical testing scheme used in statistical analysis.

The type-1 error probability was controlled across the six hypotheses (noninferiority and superiority for the primary outcome, superiority for the confirmatory secondary outcome) in a hierarchical order, beginning with non-inferiority in change in HbA1c for semaglutide 1·0 mg versus insulin glargine, followed by superiority in change in body weight for semaglutide 1·0 mg versus insulin glargine, non-inferiority in change in HbA1c for semaglutide 0·5 mg versus insulin glargine, superiority in change in HbA1c for semaglutide 1·0 mg versus insulin glargine, superiority in change in body weight for semaglutide 0·5 mg versus insulin glargine and finally superiority in change in HbA1c for semaglutide 0·5 mg versus insulin glargine. The null hypothesis for inferiority was that semaglutide 1·0 mg was inferior to insulin glargine by a margin of 0·3%; for superiority, the null hypothesis was that semaglutide 0·5 mg and 1·0 mg were not different from insulin glargine. If a null hypothesis was not rejected at any stage, testing was stopped and no further confirmatory conclusions were drawn. All p-values were two sided, testing the null hypothesis of no difference.

Supplementary Material 5. Informed consent

All subjects provided written informed consent prior to treatment initiation. All but two subjects had provided informed consent prior to any trial-related activity. However, two subjects (one randomised to insulin glargine and one who failed screening) had received screening/randomisation calls from the interactive voice/web response system prior to providing written informed consent.

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Supplementary Figure 1. Statistical sensitivity analyses.

a) Change in HbA1c

Primary analysis (MMRM) –0·38* [–0·52;–0·24] –0·81* [–0·96;–0·67]

Complete case analysis (MMRM) –0·41* [–0·55;–0·27] –0·85* [–0·99;–0·71]

In-trial analysis (MMRM) –0·34* [–0·48;–0·19] –0·68* [–0·82;–0·54]

ANCOVA (LOCF) –0·35* [–0·49;–0·21] –0·70* [–0·84;–0·56]

Per protocol (MMRM) –0·39* [–0·54;–0·24] –0·82* [–0·97;–0·68]

Pattern mixture model [1] –0·30* [–0·45;–0·15] –0·65* [–0·80;–0·50]

Pattern mixture model [2] –0·36* [–0·51;–0·22] –0·71* [–0·86;–0·57]

*Indicates significance (p-value <0·0001 for comparison with insulin glargine). Values are ETDs with 95% CIs from a MMRM analysis using ‘on-treatment without rescue medication’ data from subjects in the full analysis set, with the exception of the in-trial analysis. PMM[1]: multiple imputations were performed using a pattern mixture model with a group inferior to control group based pattern imputations. PMM[2]: multiple imputations were performed using a pattern mixture model with control group based pattern imputations. ETD, estimated treatment difference; CI, confidence interval; MMRM, mixed model for repeated measurements analysis; LOCF, last observation carried forward; IGlar, insulin glargine; PMM, pattern mixture model.

-1.0 -0.5 0.0 0.5

ETD (semaglutide – IGlar)

Favours semaglutide Favours IGlar

ETD [95% CI]

Semaglutide0·5mg Semaglutide1·0mg

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b) Change in body weight

Primary analysis (MMRM) –4·62* [–5·27;–3·96] –6·33* [–6·99;–5·67]

Complete case analysis (MMRM)

–4·54* [–5·22;–3·85] –6·45* [–7·14;–5·76]

ANCOVA (LOCF) –4·31* [–4·96;–3·66] –5·82* [–6·48;–5·17]

Pattern mixture model

–4·29* [–4·90;–3·68] –5·72* [–6·33;–5·10]

In-trial analysis (MMRM)

–4·18* [–4·84;–3·51] –5·60* [–6·26;–4·93]

*Indicates significance (p-value <0·0001 for comparison with insulin glargine). Values are ETDs with 95% CIs from a MMRM analysis using ‘on-treatment without rescue medication’ data from subjects in the full analysis set, with the exception of the in-trial analysis. ETD, estimated treatment difference; CI, confidence interval; MMRM, mixed model for repeated measurements analysis; LOCF, last observation carried forward; IGlar, insulin glargine.

-8 -7 -6 -5 -4 -3 -2 -1 0 1


ETD [95% CI]

Semaglutide 0·5 mg Semaglutide 1·0 mg

Favours semaglutide Favours IGlar

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Supplementary Figure 2. Change in Diabetes Treatment Satisfaction Questionnaire (DTSQ), ETDs at week 30.

Treatment satisfaction 0·87* [0·11;1·63] 1·38* [0·60;2·15]

How satisfied are you with your current treatment

0·03 [–0·16;0·21] 0·16 [–0·03;0·34]

How often have you felt that your blood sugars have been unacceptably high recently

–0·44* [–0·70;–0·17] –0·71* [–0·97;–0·44]

How often have you felt that your blood sugars have been unacceptably low recently

–0·02 [–0·25;0·20] –0·07 [–0·30;0·16]

How convenient have you been finding your treatment to be recently

0·20* [0·03;0·37] 0·17 [–0·00;0·34]

How flexible have you been finding your treatment to be recently

0·16 [–0·01;0·34] 0·33* [0·15;0·51]

How satisfied are you with your understanding of your diabetes

0·04 [–0·11;0·19] 0·07 [–0·09;0·22]

Would you recommend this form of treatment to someone else with your kind of diabetes

0·14 [–0·02;0·30] 0·24* [0·08;0·40]

How satisfied would you be to continue with your present form of treatment

0·28* [0·09;0·47] 0·36* [0·17;0·56]

*Indicates significance (p-value <0·03 for comparison with insulin glargine). Values are ETDs with 95% CIs from a mixed model for repeated measurements analysis using ‘on-treatment without rescue medication’ data from subjects in the full analysis set. The 8 DTSQ items are scored from 0–6. Treatment Satisfaction is the sum of 6 of the 8 DTSQ items, and ranges from 0–36.

DTSQ, Diabetes Treatment Satisfaction Questionnaire; ETD, estimated treatment difference; CI, confidence interval; IGlar, insulin glargine.

-1.0 0.0 1.0 2.0 3.0



ETD [95% CI]

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Supplementary Figure 3. Change in Short-Form 36 version 2 (SF-36v2)TM, ETDs at week 30.

Physical component summary, PCS 0·00 [–0·97;0·98] 0·91 [–0·07;1·89]

Mental component summary, MCS 0·98 [–0·28;2·25] 1·08 [–0·20;2·35]

Physical functioning 0·96 [–0·21;2·12] 0·80 [–0·37;1·97]

Role physical 0·12 [–1·12;1·36] 1·19 [–0·06;2·44]

Bodily pain 0·05 [–1·34;1·43] 0·86 [–0·53;2·25]

General health 0·33 [–0·70;1·35] 1·15* [0·12;2·18]

Vitality 0·75 [–0·49;2·00] 1·13 [–0·12;2·38]

Social functioning 0·77 [–0·52;2·06] 0·68 [–0·62;1·98]

Role emotional 0·83 [–0·63;2·29] 1·67* [0·20;3·14]

Mental health 1·15 [–0·11;2·40] 0·62 [–0·64;1·89]

*Indicates significance (p-value <0.03 for comparison with insulin glargine). SF-36v2, Short-form 36 version 2; IGlar, insulin glargine; ETD, estimated treatment difference; CI, confidence interval.

-2.0 -1.0 0.0 1.0 2.0 3.0 4.0



ETD [95% CI]

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Supplementary Figure 4. Estimated GFR, observed mean by week.

Values are observed means (+/- standard error) based on ‘on-treatment’ data from subjects in the safety analysis set. Reference range is between 77 and 179. GFR, glomerular filtration rate; MDRD, modification of diet in renal disease; IGlar, insulin glargine.

Supplementary Figure 5. Change in HbA1c, cumulative distribution function at Week 30

Data are observed values using ‘on-treatment without rescue medication’ data from subjects in the full analysis set. Missing data are imputed from a mixed model for repeated measurements analysis. IGlar, insulin glargine.

84

86

88

90

92

94

96

98

100

Estim

ated

GFR

(M

DRD

) (m

L/m

in/1

·73

m2 )

Time since randomisation (week)

Semaglutide 0·5 mg Semaglutide 1·0 mg IGlar

0

20

40

60

80

100

-5 -4 -3 -2 -1 0 1 2 3 4

Cum

ulat

ive

dist

ribu

tion

(%)

Change from baseline in HbA1c (%)


4 8 12 16 23 30 –2

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Supplementary Figure 6. Subjects discontinuing treatment prematurely due to adverse events

Adverse events are on-treatment. IGlar, insulin glargine.

Supplementary Figure 7. Estimated mean lipase (A) and amylase (B) levels by week

A

Data are observed on-treatment data

Mean lipase increased to a significantly greater extent with semaglutide 0·5 mg and 1·0 mg compared with insulin glargine (p<0·0001 for both at week 30)

0123456789

10

0 5 10 15 20 25 30

Dis

cont

inue

d su

bjec

ts (

%)



35

40

45

50

55

Lipa

se (

U/L

)

Time since randomisation (week)4 8 12 16 23 30 0


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B

Data are observed on-treatment data

Mean amylase increased to a significantly greater extent with semaglutide 0·5 mg and 1·0 mg compared with insulin glargine (p=0·0031 and p<0·0001 at week 30, respectively)

55

60

65

70Am

ylas

e (U

/L)


4 8 12 16 23 30 0


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Supplementary Table 1. Ratio to baseline for lipids at week 30.

Overall baseline*

(geometric mean [CV])

Semaglutide 0·5 mg Semaglutide 1·0 mg Insulin glargine

Ratio to baseline at Week 30 [SE]

ETR† [95% CI]

p Ratio to baseline at Week 30 [SE]

ETR† (95% CI)


Total cholesterol, mmol/L 4·52 [23·70] 0·95 [0·01] 0·96 [0·94; 0·99] 0·0038 0·95 [0·01] 0·96 [0·94; 0·99] 0·0032 0·99 [0·01]

LDL-cholesterol, mmol/L 2·35 [40·76] 0·96 [0·01] 0·94 [0·90; 0·98] 0·0053 0·95 [0·01] 0·93 [0·90; 0·97] 0·0015 1·02 [0·01]

HDL-cholesterol, mmol/L 1·16 [26·03] 0·98 [0·01] 1·00 [0·98; 1·02] 0·8331 1·00 [0·01] 1·02 [1·00; 1·05] 0·0292 0·98 [0·01]

VLDL-cholesterol, mmol/L 0·82 [52·90] 0·89 [0·02] 0·96 [0·90; 1·01] 0·1107 0·88 [0·02] 0·94 [0·89; 0·99] 0·0324 0·93 [0·02]

Triglycerides, mmol/L 1·84 [57·02] 0·89 [0·02] 0·96 [0·90; 1·02] 0·1581 0·87 [0·02] 0·94 [0·88; 0·99] 0·0295 0·93 [0·02]

Free fatty acids, mmol/L 0·84 [43·59] 0·91 [0·02] 0·98 [0·92; 1·04] 0.5487 0·91 [0·02] 0.98 [0·92; 1·04] 0·5210 0·93 [0·02] *Baseline is for the entire trial population; baseline and ratio to baseline data are geometric means (CV); †Values are ETRs with 95% CIs from a MMRM analysis using ‘on-treatment without rescue medication’ data from subjects in the full analysis set. CV, coefficient of variation; ETR, estimated treatment ratio (semaglutide versus insulin glargine); MMRM, mixed model for repeated measurements.

Supplementary Table 2. Ratio to baseline for cardiovascular risk markers at week 30.

Overall baseline*

(geometric mean [CV])

Semaglutide 0·5 mg Semaglutide 1·0 mg Insulin glargine

Ratio to baseline at Week 30 [SE]

ETR [95% CI]


ETR (95% CI)


High-sensitivity CRP, mg/L 2·50 [158·02] 0·74 [0·04] 0·77 [0·67; 0·88] 0·0001 0·62 [0·03] 0·64 [0·56; 0·74] <0·0001 0·96 [0·04]

Plasminogen activator inhibitor-1, mg/L

21·87 [62·00] 0·79 [0·03] 0·90 [0·82; 0·99] 0·0351 0·75 [0·03] 0·85 [0·78; 0·94] 0·0010 0·87 [0·03]

Data are estimated values from a MMRM analysis using ‘on-treatment without rescue medication’ data from subjects in the full analysis set. *Baseline is for the entire trial population; baseline and ratio to baseline data are geometric means (CV); CV, coefficient of variation; ETR, estimated treatment ratio (semaglutide versus insulin glargine); MMRM, a mixed model for repeated measurements.

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Supplementary Table 3. EAC-confirmed cardiovascular adverse events.

Semaglutide 0·5 mg Semaglutide 1·0mg Insulin glargine

N (%) E N (%) E N (%) E

All EAC-confirmed cardiovascular adverse events 3 0.8 3 3 0.8 4 4 1.1 4

Cardiovascular death 3 0.8 3 0 - - 2 0.6 2

Percutaneous revascularisation 0 - - 1 0.3 2 2 0.6 2

Ischaemic stroke 0 - - 1 0.3 1 0 - -

Transient ischaemic attack 0 - - 1 0.3 1 0 - -

The summary of treatment-emergent adverse events comprises treatment-emergent events with onset on or after the day of first randomised dose and not after the follow-up visit scheduled 5 weeks after end-of-treatment weeks plus the 7-day visit window for the end-of-treatment follow-up visit (42 days). E, number of events.

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Supplementary Table 4: Categories of concomitant medication according to Anatomical Therapeutical Chemical (ATC) system classes (>5% of subjects)

0.5 mg semaglutide 1.0 mg semaglutide Insulin glargine Total

Biguanides 362 (100.0) 360 (100.0) 359 (99.7) 1081 (99.9)

Sulphonylureas 186 (51.4) 185 (51.4) 187 (51.9) 558 (51.6)

HMG COA reductase inhibitors

168 (46.4) 180 (50.0) 176 (48.9) 524 (48.4)

ACE inhibitors (plain) 129 (35.6) 144 (40.0) 131 (36.4) 404 (37.3)

Platelet aggregation inhibitors (excl. heparin)

106 (29.3) 103 (28.6) 99 (27.5) 308 (28.5)

Beta blocking agents,

selective 73 (20.2) 58 (16.1) 66 (18.3) 197 (18.3)

Dihydropyridine derivatives 50 (13.8) 59 (16.4) 64 (17.8) 173 (16.0)

Angiotensin II antagonists (plain)

73 (20.2) 46 (12.8) 52 (14.4) 171 (15.8)

Proton pump inhibitors 48 (13.3) 53 (14.7) 51 (14.2) 152 (14.0)

Thiazides (plain) 46 (12.7) 40 (11.1) 36 (10.0) 122 (11.3)

Propionic acid derivatives 28 (7.7) 42 (11.7) 30 (8.3) 100 (9.2)

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Thyroid hormones 35 (9.7) 28 (7.8) 32 (8.9) 95 (8.8)

Vitamin D and analogues 32 (8.8) 22 (6.1) 29 (8.1) 83 (7.7)

Fibrates 31 (8.6) 26 (7.2) 24 (6.7) 81 (7.5)

Selective serotonin reuptake inhibitors

21 (5.8) 32 (8.9) 27 (7.5) 80 (7.4)

Other lipid modifying agents 26 (7.2) 23 (6.4) 20 (5.6) 69 (6.4)

Multivitamins, plain 20 (5.5) 23 (6.4) 19 (5.3) 62 (5.7)

Other antiepileptics 19 (5.2) 21 (5.8) 20 (5.6) 60 (5.5)

Anilides 16 (4.4) 21 (5.8) 21 (5.8) 58 (5.4)

ACE inhibitors and diuretics 18 (5.0) 20 (5.6) 16 (4.4) 54 (5.0)

Sulphonamides (plain) 19 (5.2) 13 (3.6) 18 (5.0) 50 (4.6)

Lancet Diabetes 3625 SUSTAIN 4 supplementary information ...Trial-related activities are any...

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