APPENDIX 2

Definition of Clinical Deterioration

 

The following conditions qualified as serious drug toxicity:

The following conditions qualified as major new or progressive organ disease, assessed by the treating physician as attributable to lupus or its treatment and occurring during study drug treatment or within 6 weeks post discontinuation of study drug treatment:

The following qualified as unacceptable increase in immunosuppressive or cytotoxic therapy for lupus:

 

 

 

APPENDIX 3

 

Baseline Demographics and Characteristics

(Intent to Treat Population)

 

All Patients

All Patients, Baseline SLEDAI >2

 

Placebo

N=192

GL701 200 mg

N=189

Placebo

N=146

GL701 200 mg

N=147

Mean (median) Age

44 (43)

44 (45)

44 (43)

44 (44)

Caucasian

137 (71%)

146 (77%)

99 (68%)

110 (75%)

African-American

33 (17%)

22 (12%)

27 (19%)

18 (12%)

Asian

3 (2%)

2 (1%)

3 (2%)

2 (1%)

Hispanic

16 (8%)

15 (8%)

14 (10%)

14 (10%)

Other

3 (2%)

4 (2%)

3 (2%)

3 (2%)

Post-menopausal

92 (48%)

83 (44%)

68 (47%)

63 (43%)

Pre-menopausal

100 (52%)

106 (56%)

78 (53%)

84 (57%)

Prednisone use (mg)

103 (54%)

103 (55%)

85 (58%)

83 (56%)

Immunosuppressive use

28 (15%)

32 (17%)

25 (17%)

29 (20%)

Antimalarial use

48 (25%)

44 (23%)

36 (25%)

28 (19%)

Mean (median) SLEDAI

5.8 (5.0)

6.5 (6.0)

7.3 (6.0)

8.0 (8.0)

Mean (median) SLAM

12.0 (12.0)

12.2 (12.0)

12.5 (12.0)

12.7 (12.5)

Mean (median) Patient VAS

55.4 (57.0)

55.2 (57.0)

55.2 (56.8)

57.1 (58.5)

Mean (median) KFSS

5.6 (5.7)

5.5 (5.9)

5.6 (5.7)

5.6 (5.9)

APPENDIX 4

 

Exclusions from the Per-Protocol Population

Thirty-five (35) patients were in the intent-to-treat population and not in the per-protocol population. Of these, 19 were in the GL701 group and 16 in the placebo group. These patients are described in the attached table. All but three of these 35 patients were excluded from the per-protocol patient population because they had no efficacy assessments, except at baseline. Therefore, the per-protocol population is very close to a so-called "modified intent-to-treat" population in which patients without post-baseline assessments are excluded. According to the analysis plan, such patients, without any assessments of efficacy, when analyzed in the intent-to-treat population, would by default be considered non-responders. The 3 patients with on-treatment assessments were all in the placebo group and were also excluded from the per-protocol population. One of these, patient # 18717, a non-responder, was excluded due to a major protocol violation. (She was non-compliant and did not take study drug during her first three months on study.) The other two had received less than 60 days study drug treatment, but had efficacy assessments at a termination visit. Based on the termination visit, one of these latter two was assessed as a responder, patient #43699, and the other, patient #38797, a non-responder.

 

Exclusions from the Per-Protocol Population

Patient ID

Treatment

Duration on Study Drug (days)

Reason for Exclusion

Termination Reason or Comment

12577

GL701

31

No post-baseline assessments

Mild vaginal bleeding

15635

GL701

0

No post-baseline assessments

Wanted to be treated by homeopath

15740

GL701

10

No post-baseline assessments

Abdominal bloating and worsening depression

16560

GL701

31

No post-baseline assessments

Lost to Follow-up

19453

GL701

6

No post-baseline assessments

Needed prohibited con medication for inflammatory bowel disease

19531

GL701

30

No post-baseline assessments

Pregnant

20590

GL701

38

No post-baseline assessments

Nausea, bloating, foul smelling stools

21576

GL701

125

No post-baseline assessments

Lost to follow-up. Never returned for scheduled visit, so 125 days on study drug only an estimate.

23726

GL701

22

No post-baseline assessments

Worsening of pre-existing rash, alopecia, fatigue, pleuritic chest pain

35710

GL701

10

No post-baseline assessments

Increase in shoulder and arm pain, which preceded study

35711

GL701

8

No post-baseline assessments

Wanted to participate in another study

36513

GL701

24

No post-baseline assessments

Nausea and acne

36570

GL701

48

No post-baseline assessments

Weight gain

38662

GL701

0

No post-baseline assessments

Lost to follow-up

43452

GL701

50

No post-baseline assessments

Moved

43555

GL701

69

No post-baseline assessments

Lack of efficacy

43616

GL701

35

No post-baseline assessments

Delusional thoughts and inappropriate behavior, which preceded study

43752

GL701

82

No post-baseline assessments

Depression

45585

GL701

74

No post-baseline assessments

Pregnant

13418

Placebo

46

No post-baseline assessments

Cholecystectomy

13420

Placebo

7

No post-baseline assessments

Depression, poor efficacy

15472

Placebo

21

No post-baseline assessments

Hot flashes

15517

Placebo

0

No post-baseline assessments

Lost to follow-up

15633

Placebo

100

No post-baseline assessments

Dysfunctional bleeding

18717

Placebo

365

Major protocol violation

Did not take drug for first 90 days

21409

Placebo

78

No post-baseline assessments

Septicemia

25464

Placebo

38

No post-baseline assessments

Lost to follow-up

35712

Placebo

5

No post-baseline assessments

Suicide

38501

Placebo

1

No post-baseline assessments

Lost to follow-up

38784

Placebo

106

No post-baseline assessments

Scheduling conflicts

38797

Placebo

47

Less than 60 days study drug

Moved

40630

Placebo

92

No post-baseline assessments

Fluid retention, mood swings, acne

43699

Placebo

19

Less than 60 days study drug

Increased fatigue

46730

Placebo

83

No post-baseline assessments

Non-compliant

48817

Placebo

80

No post-baseline assessments

Sudden Death

 

 

APPENDIX 5

 

Responders: Intent to Treat Population (GL95-02)

 

ITT

ITT
Baseline SLEDAI > 2

Variable

Placebo
N=192

GL701
N=189

P-value

Placebo
N=146

GL701
N=147

P-value

Improvement

Improvement

Responders (without window)

52

27.1%

58

30.7%

0.4378

42

28.8%

55

37.4%

0.1166

13.3%

29.9%

Responders

(pre-defined window)

81

42.2%

97

51.3%

P = 0.074

65

44.5%

86

58.5%

P = 0.017

21.6%

31.5%

Responders

(3% window)*

57

29.7%

75

39.7%

P = 0.041

47

32.2%

71

48.3%

P = 0.005

33.7%

50.0%

Responders

(5% window)*

63

32.8%

77

40.7%

P = 0.109

50

34.3%

72

49.0%

P = 0.011

24.1%

42.9%

Responders

(10% window)*

70

36.5%

91

48.2%

P = 0.021

56

38.4%

84

57.1%

P = 0.001

32.1%

48.7%

* Baseline mean + 3%, 5%, or 10% of patientís baseline mean

Note: Patients missing all 4 post-baseline variables were considered as non-responders in the ITT analysis.

 

Survival Analysis for First Definite Flare: Intent to Treat Population (GL95-02)

 

Intent to Treat, Baseline SLEDAI >2*

Intent to Treat**

 

Placebo

N=146

GL701 200 mg

N=147

Placebo

N=192

GL701 200 mg

N=189

Number of Patients Experiencing Definite Flare

50 (34.2%)

36 (24.5%)

57 ( 29.7%)

45 ( 23.8%)

*P-value (p=0.0967) is from a log-rank test for time to first definite flare.

**P-value (p=0.2657) is from a log-rank test for time to first definite flare.

Patients were followed up for 7 days after their last medication date.

Mean Changes in Scoring Instruments from Baseline: Intent to Treat Population (GL95-02)

 

Intent to Treat, Baseline SLEDAI > 2

Intent to Treat

Variable

Placebo

N=146

GL701 200 mg

N=147

Placebo

N=192

GL701 200 mg

N=189

SLEDAI

-2.5

-3.2

-1.7

-2.2

 

(N=134)

(N=132)

(N=178)

(N=170)

Patient VAS

-3.0

-7.2

-4.5

-6.2

 

(N=134)

(N=131)

(N=178)

(N=169)

Physician VAS

-4.3

-5.4

-5.1

-5.6

 

(N=134)

(N=131)

(N=178)

(N=169)

KFSS

-0.3

-0.3

-0.4

-0.3

 

(N=134)

(N=131)

(N=178)

(N=169)

SLAM

-2.7

-3.2

-2.7

-3.1

 

(N=134)

(N=132)

(N=178)

(N=170)

SLICC

-0.1

-0.1

-0.1

-0.1

 

(N=104)

(N=97)

(N=140)

(N=128)

SF36 - MCS

1.6

2.3

1.8

2.6

 

(N=132)

(N=129)

(N=175)

(N=166)

SF36 - PCS

0.9

1.9

1.7

1.8

 

(N=132)

(N=129)

(N=175)

(N=166)

 

APPENDIX 6

Patients Reclassified as Responders When a 3% of the Patientís
Baseline Value "Window" Is Used

ID

SLEDAI*

Patient VAS*

SLAM*

KFSS*

Baseline

Change

Baseline

Change

Baseline

Change

Baseline

Change

3429

5.00

-2.47

35.00

0.97

12.50

-6.02

5.39

-0.30

3431

5.00

0.08

58.00

-5.62

14.00

-2.00

5.94

-0.10

15414

10.00

-7.75

56.00

-13.67

12.00

-3.25

5.39

0.07

15636

8.00

-3.55

52.00

0.10

16.00

-4.39

5.11

-0.52

18724

8.00

-4.00

65.50

0.16

13.50

-3.74

7.00

-0.14

18767

4.00

-4.00

56.50

-9.50

10.50

-3.98

5.22

0.11

19498

10.00

-2.89

77.50

-0.52

12.00

0.17

5.50

-1.14

28807

14.00

-10.50

61.50

1.21

11.00

-6.00

5.89

-0.52

35654

2.00

-2.00

77.00

-10.59

11.50

-2.30

6.00

0.03

36525

4.00

-0.49

64.50

-27.50

13.00

-4.05

4.72

< 0.01

36571

7.00

-3.01

65.50

-5.13

7.50

-1.83

6.06

0.02

37496

8.00

-0.99

35.50

-5.61

9.00

-2.43

3.06

0.05

38402

12.00

-11.54

60.00

-11.31

11.50

-0.12

6.72

0.12

38404

4.00

0.11

63.00

-27.95

15.00

-1.23

4.78

-0.91

38606

4.00

-0.45

63.50

-11.28

14.00

0.42

6.50

-0.09

38734

4.00

0.00

51.50

-5.50

11.00

-2.50

5.94

0.17

41535

12.00

-2.01

70.00

-22.68

10.00

0.24

5.89

-1.62

45588

9.00

-4.13

71.00

0.31

15.00

-1.52

6.61

-0.29

45598

16.00

-9.24

75.00

0.66

16.00

-2.13

5.94

-0.71

45600

12.00

-8.00

53.00

-1.00

14.50

-3.50

5.94

0.06

49802

6.00

-4.69

78.50

-10.28

11.50

-3.93

6.67

0.13

49803

4.00

-3.50

68.00

-5.79

10.00

-0.03

5.89

0.05

*BOLDED ITALICIZED numbers indicate change from baseline for individual scores within the 3% window that would lead to re-classification from non-responder to responder.

 

 

 

 

APPENDIX 7

 

Early Termination due to Safety Concerns, Adverse Events or Death

All randomized patients from GL94-01 and GL95-02

Patient

Treatment Group

Reason for Early Termination

18141

Placebo GL94-01

Hospitalized for pneumonia

19131

Placebo GL94-01

Menometrorrhagia

27206

Placebo GL94-01

Large decubiti, bactermia, hemolytic anemia

43699

Placebo GL95-02

Fatigue increased

15472

Placebo GL95-02

Hot flashes

40630

Placebo GL95-02

Acne, mood swings, fluid retention

38736

Placebo GL95-02

Rash

3507

Placebo GL95-02

Hepatitis

43602

Placebo GL95-02

Weight gain

43538

Placebo GL95-02

Lupus flare - skin rash

25462

Placebo GL95-02

Weight gain

43614

Placebo GL95-02

Suicidal depression

36638

Placebo GL95-02

Pregnancy

15634

Placebo GL95-02

Pseudotumor cerebri

20511

Placebo GL95-02

Pulmonary HT and fibrosis

21409

Placebo GL95-02

Septicemia

33444

Placebo GL95-02

Chest pain due to coronary artery spasm

35712

Placebo GL95-02

Suicide

36685

Placebo GL95-02

Carcinoma of the lung

37495

Placebo GL95-02

Suicide

48817

Placebo GL95-02

Sudden death, possibly due to arrthmia

15295

100 mg GL94-01

Viral Hepatitis C

16191

100 mg GL94-01

Nausea and hip pain

17176

100 mg GL94-01

Vasculitis

22169

100 mg GL94-01

Hirsutism/acne

3152

200 mg GL94-01

GI bleed secondary to NSAIDs

14109

200 mg GL94-01

Headache, nausea, back pain, spasm

21197

200 mg GL94-01

Decreased WBCs, increased LFTs

21201

200 mg GL9401

Sores on buttock

24275

200 mg GL94-01

Worsening rash, alopecia, purpura, increased prednisone dose

28301

200 mg GL94-01

Facial dermatitis

35710

200 mg GL95-02

Myalgias

15740

200 mg GL95-02

Depression/abdominal bloating

36513

200 mg GL95-02

Nausea/acne

12577

200 mg GL95-02

Vaginal bleeding

 

Patient

Treatment Group

Reason for Early Termination

43616

200 mg GL95-02

Psychosis/delusional thoughts

20590

200 mg GL95-02

Nausea/bloating, foul smelling stools

36570

200 mg GL95-02

Weight gain

20684

200 mg GL95-02

Metrorrhagia

43752

200 mg GL95-02

Dyspepsia

25461

200 mg GL95-02

Depression

38403

200 mg GL95-02

Acne

19530

200 mg GL95-02

Menorrhagia

35653

200 mg GL95-02

Hirsutism

46695

200 mg GL95-02

Syncope

18670

200 mg GL95-02

Worsening alopecia

13761

200 mg GL95-02

Acne/hirsutism

43700

200 mg GL95-02

Acne/hirsutism

45600

200 mg GL95-02

Acne

15416

200 mg GL95-02

Pulmonary edema

38716

200 mg GL95-02

Abdominal pain

25595

200 mg GL95-02

Acne

33705

200 mg GL95-02

Acne/hirsutism

18618

200 mg GL95-02

Mood change/facial hair growth

3431

200 mg GL95-02

Depression

43554

200 mg GL95-02

Fluid retention, insomnia, leg pain, renal deterioration

38631

200 mg GL95-02

Acne/hirsutism

32468

200 mg GL95-02

Weight gain

36640

200 mg GL95-02

Mild depression

38421

200 mg GL95-02

Epigastric tenderness

43744

200 mg GL95-02

Breast mass (benign on biopsy)

41440

200 mg GL95-02

Arthritis/hirsutism/oily skin

 

APPENDIX 8

Narratives for Patients that Experienced a Clinically Significant Increase in Proteinuria

Patient 27208 (Study GL94-01, placebo): This patient had pre-existing renal disease and had undergone a renal biopsy prior to study. Her 24-hour urine protein increased from 1327 at baseline to 5067 mg/24 hours at the last on-treatment visit. Baseline C3 was 67 mg/dl; C4 was 10 mg/dl (nl >12 mg/dl). During the study, in addition to progressive proteinuria, new hematuria developed (0 baseline; 7 at last visit). Due to her progressive renal disease, she underwent another kidney biopsy during the study which revealed focal proliferative lupus glomerulonephritis, and she was treated with cyclophosphamide. She completed 7 months of study medication. However, her serum creatinine was stable, 1.1 at both baseline and last visit.

Patient 14483 (Study GL95-02, placebo): Her 24 hour urine protein increased from 1500 mg at baseline to 4200 mg/24 hours at the last on-treatment visit. Adverse events of proliferative glomerulonephiritis and nephrotic syndrome were reported. She was treated with cyclophosphamide and terminated study early. She developed new hematuria, with 27 RBC/hpf at last visit. Her serum creatinine increased from 1.1 to 1.3 at her last on-treatment visit. However, her serum creatinine rose to 9.2 three months later, approximately 6 weeks following end of treatment.

Patient 20511 (Study GL95-02, placebo): Her 24 hour urine protein increased from 2743 mg at baseline to 4700 mg/24 hours at the last on-treatment visit. Increased pitting edema due to active nephritis was noted as an adverse event. A kidney biopsy on treatment demonstrated lupus proliferative glomerulonephritis, which was treated with steroids and azathiaprine. She was subsequently hospitalized for refractory hypertension and pulmonary hypertension. She had a final hospitalization for acute shortness of breath, and died of cardiac arrest. Serum creatinine rose during study from 1.1 at baseline to 1.5 at final visit.

Patient 38605 (Study GL95-02, placebo): Her 24 hour urine protein increased from 1500 mg at baseline to 4200 mg/24 hours at the last on-treatment visit. An adverse event of proteinuria was reported and she was treated with increased corticosteroids for her proteinuria. However, her serum creatinine only increased from 0.9 to 1.2 at end of treatment. She completed 12 months of study medication.

Patient 30265 (Study GL94-01, GL701 100 mg): Her 24 hour urine protein increased from 3498 mg at baseline to 9713 mg/24 hours at the last on-treatment visit. Hematuria was noted during the study with baseline 0 and last visit of 16 RBC/hpf. Creatinine increased form 1.1 at baseline to 3.0 at last visit. Nephrotic syndrome was noted as an adverse event and she was withdrawn from the study to initiate treatment with cyclophosphamide.

Patient 13103 (Study GL94-01, GL701 200 mg): Her 24 hour urine protein increased from 4794 mg at baseline to 10,884 mg/24 hours at the last on-treatment visit. Baseline C3 was low at 81 mg/dl while C4 was 14 mg/dl; at last visit they were 58 and 15 mg/dl. Creatinine rose from 1.3 at baseline to 1.8 mg/dl at last visit. This patient was withdrawn from the study to undergo treatment with cyclophosphamide.

Patient 19454 (Study GL95-02, GL701 200 mg): Her 24 hour urine protein increased from 656 mg at baseline to 11423 mg/24 hours at the last on-treatment visit. C3 and C4 complement were both low at baseline with C3 of 52 mg/dl and C4 of 9 mg/dl. Both remained low with last visit values of 45 and < 10 mg/dl. Serum creatinine increased from 1.3 mg/dl at baseline to 1.9 mg/dl at last visit. Blood cells in urine increased from 0 at baseline to 42/hpf at last visit.

Patient 20770 (Study GL95-02, GL701 200 mg): This patient had undergone a renal biopsy prior to entering into the study. Her 24 hour urine protein increased from 2329 mg at baseline to 10415 mg/24 hours at the last on-treatment visit. C3 complement at baseline was low at 57 mg/dl while C4 was normal at 12 mg/dl. At last visit, C3 and C4 were 34 and <10 mg/dl, respectively. Urine RBCs increased from 2/hpf at baseline to 19/hpf at last visit. She experienced a renal flare during the study and required treatment with mycophenolate mofetil (Cellcept) at study termination. However, her serum creatinine was 0.7 at baseline, and 0.9 at the on treatment visit.

Patient 23485 (Study GL95-02, GL701 200 mg): Her 24 hour urine protein increased from 527 mg at baseline to 1090 mg/24 hours at the last on-treatment visit. C3 at baseline was 84 mg/dl, C4 was 16 mg/dl. At last visit, they were 79 and 13 mg/dl. Her serum creatinine was 1.2 at baseline, and 1.0 at the on treatment visit. The patient was terminated from study drug prematurely in order to undergo treatment with cyclophosphamide for lupus nephritis.

Patient 36514 (GL701 200 mg, Study GL95-02): Her 24 hour urine protein increased from 1319 mg at baseline to 2574 mg/24 hours at on-treatment visit. Serum creatinine was 1.6 mg/dl at baseline and 1.8 mg/dl at last visit. She was hospitalized, after 8 months on study, for a renal biopsy which revealed focal proliferative glomerulonephritis. The diagnosis at that time was labile hypertension and chronic renal failure. Her serum creatinine during the hospitalization ranged from 2.2 to 2.6 mg/dl; her creatinine clearance was 53.3. Study drug was discontinued to allow treatment with increased steroids and immunosuppressives.

Patient 38445 (Study GL95-02, GL701 200 mg): Her 24 hour urine protein increased from 2420 mg at baseline to 4648 mg/24 hours at the last on-treatment visit. Her corticosteroid dose was increased because of the proteinuria. However, her serum creatinine was stable, 1.1 at both baseline and last visit. Serum C3 decreased from 87 to 60. She did not complete 12 months study medications.