# Presentation: 276682

## INTRODUCTORY REMARKS

## CHALLENGES IN STUDY OF DRUG EFFECTS IN LUPUS

- Multiple organ / tissue manifestations
- Variable short and long term course
- Mixture of pathology - disease and drug toxicity
- Disease activity indices
- Treatment malleability (esp. steroids)

## LUPUS TRIALS  

- Disease activity assessment in lupus
- SLEDAI, SLAM, BILAG, ECLAM (others: SIS, LAI; some updated)*
- RCT assessment (domains)
- activity
- damage
- drug toxicity
- health related quality-of-life
-        *ref: Strand JRheum 26:490, 1999

## SLE Disease Activity Index SLEDAI 

- Derivation: Toronto (1992), Delphi process of physicians/statisticians (Bombardier: A&R 35:630)
- Metric: static measure; timeframe=10 days
- Content: 24 components, weighted (four categories: 1, 2, 4, 8; fatigue / steroid use not included.

## SLEDAI Components / Weights

- 8	seizure, psychosis, organic brain syndrome, visual disturbance, cranial nerve disorder, lupus headache, CVA, vasculitis
- 4 	arthritis, myositis, urinary casts hematuria, proteinuria, pyuria
- 2 	rash, alopecia, mucosal ulcers, pleurisy, pericarditis, low complement, high DNA
- 1	fever, low platelets, low WBC

## Systemic Lupus Activity Measure: SLAM

- Derivation: Boston (1989) Judgment re. components of 1983 ACR definition of lupus, plus patient and physician VAS global (Liang:A&R 32:1107)
- Metric: static measure; timeframe=1 month
- Content: 2 globals, 24 clinical, 7 laboratory, 1 “other” component; weighted (_<_ 4 categories: absent --> severe); fatigue included; steroid use not.

## SLAM Components by System

- 3 Constitutional (incl. fatigue)
- 4 Integument
- 3 Eye
- 2 Reticuloendothelial
- 2 Pulmonary
- 3 Cardiovascular
- 1 Gastrointestinal
- 5 Neuromotor
- 1 Joints
- 7 Laboratory
- + 1 “other” + 2 globals = 34 in TOTAL

## British Isles Lupus Assessment Group: BILAG

- Derivation: UK (1988) Consensus of physicians regarding trigger to change therapy (QJMed 69:927, & 86:447)
- Metric: Transition measure (4 states)
- “Action” = urgent need for DMARD (high dose steroids or immunosuppressive rx)
- “Beware” = watch +/- low dose steroids / HCQ
- “Content” = static or inactive
- “Dull” = no involvement
- Content: 8 organ systems, weighted: A=9, B=4, C=1, D=0; fatigue / steroid use included.

## European Consensus Lupus Activity Measure: ECLAM

- Derivation: Europe (1992) - Optimization of statistical model of patient (704) database from 14 countries, using MD global as gold standard (Clin Exp Rheum 10:5541)
- Metric: static measure; time frame=1-3mo
- Content: Fatigue included; steroid use not

## Performance Characteristics (“Validation”) 

- Intrinsic content
- validity (“truth” per Omeract filter)
- reliability  (“discrimination”)
- responsiveness to change (“discrimination”)
- feasibility (“feasibility”)
- Extrinsic setting
- observational studies (cohort)
- controlled trials***

## Recent trials in mild-moderate lupus (not lupus nephritis)

- Canadian HCQ v PLC (NEJM 324:150, 1991)         n=47     6mo
- design/analysis: withdrawal/survival
- endpoint: time to clinical flare / severe exacerbation
- CSSRD HCQ v PLC (JRheum 21:1457, 1994)        n=71       1yr
- design/analysis: standard/comparison of means
- endpoints: many (publication: 4 grades of arthritis)
- Brazilian MTX v PLC (JRheum 26:1275, 1999)     n=41      6mo
- design/analysis:standard+pred. change/comparison means
- endpoints = SLEDAI, pain VAS, (prednisone use)

## Other DHEA RCTs in lupus 

- 3mo, mild-mod lupus, n=28 (van Vollenhoven, A&R 38:1826,1995)
- endpoints=SLEDAI, globals, prednisone dose
- 6mo, severe lupus, n=21 (vanVollenhoven, Lupus 8:181,1999)
- EP=stabilization (w/o new rx) of primary organ involvement (nephritis, hematologic, serositis)
- 6mo, mild-mod lupus, n=120 (Taiwan-see my review)
- endpoint=mean change in SLAM at 6mo
- GL97-01-ongoing: 12 mo, male lupus, n=40

## Early Discussions   

- Two trials
-   94-01	191 patients, 3 arms: 200mg,100mg, plc
-   95-02	381 patients, 2 arms: 200mg, plc
- Steroid sparing = meaningful endpoint (would carry evidentiary weight in an NDA)
- By-patient assessments offer both less controversy about interpretation AND more clinically intuitiveness to patient and doctor
- Dimensions of the overall safety database

## MEDICAL REVIEW

## Outline 

- Comments on designs: 94-01 and 95-02
- Population characteristics: 94-01 and 95-02
- Efficacy results: 94-01 and 95-02
- Discussion of SLEDAI>2 signal
- Safety

## Design: Trial 94-01

- Steroid-sparing design - few precedents
- inherently more variable because one is measuring “downstream” from signs and symptoms
- “Steroid stuck” patients - difficult to define
- failed taper w/in 12mo + stable x 6wk, or
- no failed taper but stable x 3mo

## Design: Trial 94-01

- Two “primary” endpoints
- 1: Achieving durable reduction to physiological dose prednisone (7.5mg/d)
-        “Subpart E endpoint”
-        Clinically more demanding endpoint, but not
-                a essential one
- 2: Mean % change in prednisone dose
-         potentially more sensitive endpoint

## Design: Trial 94-01

- Timeline
- first patient enrolled		June 6, 1994
- last patient completed	May 28, 1996
- blind broken			April 21, 1997
- Amendment, March 21, 1997
- added baseline SLEDAI to covariates for primary analysis (logistic regression model)

## Patients: Trial 94-01

-                                GL701-200 GL701-100   PLC
- 				       (n= 64)       (n=63)       (n=64)
- age			              40             40            41
- race (%w/b)	            55/27       57/25       69/27
- pre-menopausal (%)      75            59            59
- prednisone (mg)            13.7        13.7         15.2
- entry SLEDAI              5.9           5.3           6.4

## Withdrawals: Trial 94-01Survival analyses

-                                P values*
-                    200mg v PLC    100mg v PLC
- all cause		0.80			0.74
- inefficacy		0.50			0.77
- adverse event	0.35			0.71
-                              *log rank

## Efficacy results: Trial 94-01

- 1st primary endpoint (durable pred_<_7.5mg)
- GL701 200mg	35/64	(55%) 	p=0.11
- GL701 100mg	28/63	(44%) 	p=0.66
- PLC			26/64 (41%)
- 2nd primary endpoint (% change pred.)
-                                        mean         median
- GL701 200mg	     30% 	      53%
- GL701 100mg	     14% 	      41%
- PLC			     36% 	      50%

## SLEDAI>2 subset: Trial 94-01(Hypothesis generating)

- 		 Achieving durable prednisone
-         200mg vs plc	 	p=0.18*
-         100mg vs plc		p=0.75
- 	   *adjusted for baseline prednisone; unadjusted p=0.031

## SLEDAI>2 subset: Trial 94-01

-               Mean % change in prednisone					       					       					        mean       median
-     200mg GL701 arm		22%            50%
-     100mg GL701 arm		  0%            33%
-     placebo arm 			26%            33%

## SLEDAI categories: Trial 94-01ENDPOINT= % responders

- 			       GL701-200 GL701-100  PLC
- 				(n=64)         (n=63)     (n=64)
- SLEDAI
-      0-2		 63 (12/19)      62 (10/16)    68 (13/19)
-      2-4                 56 (5/9)        44 (8/18)     33 (5/15)
-      4-8                 50 (12/24)     44 (7/16)      31 (4/13)
-       >8                 50 (6/12)       23 (3/13)     23 (4/17)
-                 Note: small numbers

## SLEDAI Categories: Trial 94-01 ENDPOINT= mean % change of prednisone from baseline

- 			     GL701-200 GL701-100  PLC
- 				 (n=64)       (n=63)    (n=64) SLEDAI
-        0-2		   50		    54           60
-        2-4                  47               23           20
-        4-8                  18               10           30
-         >8                  11               44           27
-                       Note: small numbers

## Design: Trial 95-02

- By-patient, dichotomous endpoint but used logistic regression model to incorporate covariates
- Endpoint designed to capture totality of drug effect (no precedents)
- Prednisone fixed (unlike Trial 94-01)
- Started before Trial 94-01 completed

## Endpoints: Trial 95-02

- Primary endpoint = “responder,” defined as
- no deterioration in 4 measures - SLEDAI, SLAM, Krupp Fatigue Severity scale (KFSS), and patient global (PG),
-                                PLUS
- no “clinical deterioration” (long list)
- Secondary endpoint = mean change from baseline in 4 variables (SLEDAI, SLAM, KFSS, PG)

## Design: Trial 95-02

- Timeline
- first patient enrolled		March 7, 1996
- last patient completed	April 2, 1999
- Amendments
- August 4, 1997: increase enrollment by 50 and require SLEDAI>2 for entry
- April 21, 1999: instituted a uterine / breast monitor program for post-menopausal patients
- Statistical Analysis Plan - next slide

## Statistical Analysis PlanTrial 95-02

- Communications during 1998 and 1999
-       modified population using SLEDAI>2
-       modified responder definition (“window”)
-       modified population using 60d treatment
- Final version: April 30, 1999

## Patients: Trial 95-02

-                                            GL701	 PLC
- 					      (n=189)      (n=192)
- age				         44.4		  43.8
- race (%w/b/other)	     77/12/11     71/17/12
- pre-menopausal (%)             56	            54
- mean pred. dose (mg)           3.5	            3.7
- cytotoxic rx (%)	                   17                15
- baseline SLEDAI            6.6 (0-18)   5.8(0-24)

## Withdrawals: Trial 95-02Survival analyses

-                	            PLC vs GL701
-                                     P value*
- all cause		            0.08
- inefficacy			   0.53
- adverse event		   0.04
-                               *log rank

## Efficacy results: Trial 95-02

- Primary (all-randomized) analysis - “responders” by protocol definition
- GL701			58/189 (31%)    p=0.436*
- PLC			52/192 (27%)
-                                   * logistic regression
- Secondary analyses
- mean change in 4 parameters, and investigator global, SF36 -- all with p>0.25 (see next slide)
- time to withdrawal (all cause), by log rank -- p=0.08 trend in favor of PLC

## Efficacy results: Trial 95-02

-                      Secondary endpoints
- 				   GL701	  PLC    P value
- SLEDAI		     -2.2           -1.8       0.25
- SLAM		     -2.9	  -2.9       0.38
- KFSS		     -0.3           -0.3       0.45
- PG 		     -5.1           -4.7       0.86

## SLEDAI>2 Patients (n=293) Trial 95-02

- No. of responders
- GL701: 55/147				p=0.127
- PLC: 42/146
- Individual measures (mean change)
- SLEDAI				p=0.15
- SLAM					p=0.19
- KFSS					p=0.61
- PG					p=0.06

## SLEDAI>2 + Rx>2mo Patients (n=265) Trial 95-02

-                     No. of Responders
-     GL701				56/132
-     PLC				42/133
-                            p=0.068

## Same subset (SLED>2, rx>2mo)Using modified window (n=265) Trial 95-02

-                     No. of Responders
-     GL701				87/132
-     PLC				65/133
-                           p=0.005

## Summary: Responder AnalysesTrial 95-02

- All patients			n=381      p=0.436
- 58/189 vs 52/192
- Subset: >60d rx 			n=346      p=0.254
- 60/170 vs 52/176
- Subset: SLEDAI>2		n=293      p=0.127
- 55/147 vs 42/146
- Subset: >60d rx, SL.>2	n=265      p=0.068
- 56/132 vs 42/133
- 87/132 vs 65/133  (new window)		           p=0.005

## Safety- general

- Per this database
- physiologically expected - hormonal effects
- abdominal pain signal? -  from one trial
- renal signal? - needs further exploration
- Background aspects to the overall database
- effects of chronic hormonal exposure
- long-term consequences of lipid alterations

## Adverse Events with p<0.05Trial 94-01

-                      GL701-200  GL701-100     PLC
- acne		   	 44%*          44%*         12%
- abdominal pain  	 22%*          11%             6%
- hypertension	 13%*            3%             2%
- stomatitis	          16%            24%*           9%
- LE rash		   6% 	  14%           20%*
- sinusitis		   8%              6%          20%*
-      *statistically significant greater event rate

## Adverse Events with p<0.05*Trial 95-02

-                                    GL701        PLC
- acne		           	33%*          14%
- hirsutism                     16%*            2%
- stomatitis                    15%            23%*
- myalgia                       22%            36%*
-         *statistically significantly greater event rate

## OUTSTANDING ISSUES REGARDING THE WEIGHT OF THE EVIDENCE

- Consistency of results across endpoints
- Is analysis of withdrawals a method to balance efficacy and safety?
- Which analyses rise, on clinical grounds, to a level of importance here?

## EXTRA SLIDES

## SLEDAI Categories: Trial 95-02

-            % responders (primary endpoint)
-                               GL701              PLC
- 				  (n=189)           (n=192)
- SLEDAI
-     0-2	         7% (3/42)	     22% (10/46)
-     2-4                31% (9/29)      28% (11/40)
-     4-8               46% (30/65)     35% (24/68)
-     >8                30% (16/53)      18%  (7/38)

## KJ extra: Risk / benefit

- Will the indication, if demonstrated, have shrunk so much as to suggest inadequate R/B?	e.g. women / pre-menopausal / with mild-mod disease / SLEDAI>2 / ...
- If a clear efficacy demonstration were made  in a major clinical subset of lupus, what overall database size (#/duration) and characteristics are reasonable?

## KJ extra: Moving forward

- Dredging this database
- by dominant organ involvement at outset
- further explore DHEA-S levels and presence (or recent use) of prednisone re. response
- Make data available to academic methodologists interested in lupus measurements - will move much slower w/o
- Closely look at the kidney - ensure not renal lupus signal (w/ another pilot, if needed)

## KJ extra: Moving forward - caution

- DHEA may have a physiological role in counteracting (hormonally, somehow) some lupus features, but it may have an equally predictable physiologic toxicity profile which engages just as early (or earlier) and,   essentially, counterbalances efficacy all along the way.

## KJ extra: Additional RCTs - preparatory

- Assess loss of information with dichotomous outcomes versus clarity of statistics (and interpretability to naïve clinicians
- Readdress “steroid stuck”
- Get “domain” agreement (like w/ OA)
- control of experiment wide alpha (multiplicity)

## KJ extra: Lupus RCTs - intrinsic problems

- Need direct, public discussion of RCT design/conduct/analysis/interpretation issues in lupus  -- what venues?
- Biggest issues, in my mind
- face validity for lupus (can’t adapt from other settings)
- controlling experiment-wide alpha (i.e. multiplicity)