# Presentation: 662440

## FDA AAC: Discussion of 

**SLE Concept Paper**
**State of the Art: HRQOL, Fatigue and Function**

**Vibeke Strand, MD****Biopharmaceutical Consultant**
**Adjunct Clinical Professor, **
**Division of Immunology, Stanford University**

## Disclosures

- Abbott
- Alexion
- Amgen Corporation
- Aventis Pharmaceuticals
- Celltech
- Centocor
- Genelabs
- Genentech
- Genzyme
- Hoffman LaRoche
- IDEC
- Incyte
- La Jolla Pharmaceuticals
- Novartis
- Pfizer
- Procter and Gamble
- Scios
- SKK
- SumitomoXoma Corporation

- Abgenix
- Affymax
- Alza Corporation
- Astra Zeneca
- Becton Dickinson
- Biogen
- Boeringher Ingelheim
- Entelos
- Geron, Inc.
- Glaxo SmithKline
- Immune Response Corp
- RWJohnson PRI
- Eli Lilly and Co
- Medarex
- Organon
- Otsuka
- Schering Plough
- Targeted Genetics

- 	Current Clients	Previous Clients

## Lessons Learned: It is Difficult to Assess Outcome in SLE RCTs

- Disease Activity Indices do NOT necessarily reflect OUTCOME
- Disease activity ≠ Disease severity
- Variability in weighting different organ manifestations
- Variability in scoring and scoring items [eg, fatigue]
- Only BILAG designed to reflect need for change in treatment
- Few have been used / validated in RCTs
- Poor correlation between patient and physician assessments of 	disease activity
- Responder analyses do NOT function well if they are 	proposed in absence of data from RCTs
- Changes in medical practice may confound treatment effects

## OMERACT 4 SLE Module 1998Goal

- To develop consensus on required outcome domains 	to be assessed in clinical trials in SLE:  	Randomized Controlled Trials   [RCTs] and/or 	Longitudinal Observational Studies   [LOS]
- Organizing Committee: 	D. Gladman				D. Isenberg 				M. Petri	 				J. Smolen 				V. Strand

**Strand et al:  J Rheum 1999; 26: 490-497**
**Smolen et al:  J Rheum 1999; 26: 504-507**

## Outcome Domains Recommended by OMERACT 4

**Strand et al:  J Rheum 1999; 26: 490-497**
**Smolen et al:  J Rheum 1999; 26: 504-507**

- Disease activity:
- Damage:
- HRQOL:
- Should also include:
- Adverse events
- Economic costs including health utilities

## What is Health Related Quality of Life?

- NOT the economy...
- NOT the geopolitical situation...
- NOT status or access to resources...
- “In all the ways your disease affects you, 	how are you doing today?”
- SLE affects all domains of health related quality of life
- Patients complain of fatigue, 			          inability to plan ahead, and			          changes in appearance

## SF-36: Short Form 36 Health Survey

- Validated, widely used generic measure of HRQOL
- 8 Domains:
- Scored 0 - 100; age, gender adjusted norms
- 2 Summary Scores: Normative based scoring
- Mean: 50, SD: 10
- Physical Component: PCS
- Measures how decrements in physical function 	affect day to day activities
- Impact of physical impairment / disability on HRQOL
- Mental Component: MCS
- Impact of mental affect, symptoms of pain on HRQOL
- Facilitates comparison with other disease states

## SF-36 Domains and Summary Scores

- Physicalcomponent

**SF-36 Domains and Summary Scores**

## SLE Impacts all Domains of HRQOL

- Coping mechanisms most consistently associated with HRQOL, but not morbidity– Ethnicity and socioeconomic status are important – Variable
- Social support consistently associated with reported	mental health
- Organ damage less associated with reported HRQOL	than disease activity
- Data in patients receiving care from rheumatologists:
- In cohort studies or enrolled in RCTs
- May underestimate influences of access to care and 	treatment adherence

**Sutcliffe et al: Rheumatol 1999; 38:1130-7****Ward: Arth Rheum 2001; 44:2711-4**

## Disability in SLE Encompasses all Domains of HRQOL

- Fatigue and  Depression important — 	and are quantifiable
- Disease activity, damage ± health related quality of life
- Disability ± Impairment in physical function:
- 106 SLE pts in Baltimore: mean HAQ DI = 0.66
- > 25% had HAQ DI scores of 0
- <10% required assistance or assistive aids
- 120 SLE pts in Cleveland: mean HAQ DI = 0.83
- 125 in Canada: mean HAQ DI = 0.61

**Hochberg et al JRheum 1988; 15:959-964**

**Milligan et al JRheum 1993: 20:972-6**
**Gladman et al: Lupus 1996; 5:190-5**

## HRQOL in SLE compared with RA

- RA and SLE patients complain of: 	loss of energy, 		unpredictable course of disease
- SLE patients complain of fatigue; ‘inability to plan ahead’
- SLE patients have more dissatisfaction with perceived 	control of their bodies, and body image
- SLE patients dissatisfied with understanding about their 	condition on the part of MDs and other individuals
**«Handicap invisible to others»**

**Burckhardt et al JRheum 1993; 20:997-81****Archenholtz et al: Qual Life Res 1999; 8:411-6**

## HRQOL in SLE Compared with RA

- Prospective study of 82 patients with RA, 82 with SLE	matched for age, gender, disease duration	and 74 age and gender controls
- Both diseases impact all dimensions of health status
- Less disability in RA, and lower VAS pain scores– but no difference in bodily pain domain scores
- SF-36 correlated best with:	patient global assessment	accumulated damage index

**Gilboe et al JRheum 1999; 26:1694-700**

## SF-36: Short Form 36 Health Survey

- Baseline domain scores low in SLE
- v. age/gender norms for Canada, Norway, UK, US
- v. serious medical problems (IDDM, CAD)
- In cohort studies reflects changes in disease activity 	(SLAM, BILAG, SLEDAI):
-   disease activity in PF, BP, GHP
-  disease activity  SF-36 domain scores, esp. PF
-  damage in PF, GHP

**Gladman et al: J Rheum 1995; 23:1953-5**

**Gordon et al: A+R 1997; 40:487   Gladman et al: Clin Exp Rheum 1995; 14:305-8**
**Stoll et al: J Rheum 1997; 24:309-13 and 1608-14   Fortin et al: Lupus 1998; 7:101-7**
** ****Sutcliffe et al: J Rheum 1999; 26:2352-6  Wang et al: J Rheum 2001; 28: 525-32**

## SF-36 is Sensitive to Change in SLE

- Demonstrated valid and sensitive to change 	in RCTs and LOS in SLE
- Decrements in multiple domains correlate with increases 	in disease activity and damage 	– although generally weak correlations
- Immunosuppressive use
- Reflect ESRD

**Abu-Shakra et al J Rheum 1999; 26:306-9**
**Thumboo et al J Rheum 1999; 26:97-102****Thumboo et al J Rheum 2000; 27:1414-20**
**Wang et al J Rheum 2001; 28:525-32                                   **

**Stoll et al: J Rheum 1997; 24: 309-13 and 1608-14**** **
**Fortin et al: Lupus 1998; 7:101-7**** **** **
**Sutcliffe et al: J Rheum 1999; 26:2352-6****   ****Strand et al: J Rheum 1999; 26:495-503  **
**Thumboo et al: J Rheum 2000; 27:1414-1420**
**Wang et al: J Rheum 2001; 28: 525-32**

**Rood et al J Rheum 2000; 27:2057-9**

**Vu, Escalante ****J Rheum 1999; 26:2595-2601**** **

## SF-36 is Sensitive to Change in SLE

- Changes in domain scores in general best correlated 	with changes in disease activity, higher 	glucocorticoid doses, use of cytotoxic agents
- Greatest variability in Role Physical and Role Emotional 	domains
- Taking the mean of the 4 physical domains = PHSand 4 mental domains = MHS
- PHS negatively correlated with  ↑ steroid doses					      ↑ BILAG score
- MHS negatively correlated with  ↑ steroid doses 					                 use of cytotoxics					      ↑ BILAG scores

**Thumboo et al J Rheum 1999; 26:97-102****Thumboo et al J Rheum 2000; 27:1414-20**

## Minimum Clinically Important Differences[MCID]

- Degree of improvement in various  outcome measures
- Perceptible to patients
- Considered clinically important / meaningful
- Defined by patient query, delphi technique	HAQ DI: 0.22 improvement
- Confirmed by statistical correlations with clinical responses 	in placebo RCTs, using patient global assessments
- When group median (and mean) changes well exceed 		MCID, it can be expected that a majority of patients 	will attain clinically meaningful improvement

## Minimum Clinically Important Differences [MCID]

**Wells et al. J Rheumatol. 1993; 20:557-60 **
**Guzman et al. Arth Rheum. 1996; 39:5208**
**Kosinski et al. Arth Rheum. 2000; 43:1478-87**
**Samsa et al. Pharmacoeconomics. 1999; 15:141-155 **
**Thumboo et al. J Rheumatol. 1999; 26:97-102.**
**Zhao et al: Pharmacotherapy 1999; 19:1269-78**
**Angst et al: Arth Care Res 2001; 45:384-91**

**Minimum Clinically Important Differences ****[MCID]**

-      HAQ DI 1-4	     0 - 3	  –	0.22
-      SF-36 2, 4-8	        0 - 100	  +	5 - 10 points
-      PCS/MCS mean 	  50 ± 10	  +	2.5 - 5 points

- 	Score	Direction			MCID
- 	Range	 of Scoring

## Other Points: Confounding Issue of Fatigue

- 2° to active SLE or fibromyalgia?
- Associated fibromyalgia in cohort series:
- Petri:			 	25 - 30%
- Gladman:			20%
- Gordon, Isenberg:		<10%
- Capable of treatment independent of SLE?
- Significantly impacts SF-36,
- Other patient reported measures?
- Fatigue assessed by MD included in SLAM; SLAM-R
- Krupp Fatigue Severity Score reflects alterations
- NOT 2° to psychological stress
- Different than reported in other ds states, eg MS

**Gladman et al J Rheum 1997; 24:2145-8****Taylor et al A+R 1998: 41: 1797-85**

**Krupp et al Arch Neurol 1989: 46: 1121-3**

## Αnti dsDNA Ab levels Predict Disease Flares

- Swaak: in 143 SLE patients followed for up to 6 years:
- 2x **↑** αdsDNA Ab levels within 10 weeks predicted 33 major 	‘exacerbations’: 21 renal; 12 non-renal
- 80% renal ‘flares’ predicted by **↓** C4 levels
- Ter Borg: in 17/72 SLE patients followed over mean 18.5 months
- 24/33 ‘exacerbations’ predicted by **↑** αdsDNA Ab levels
- 13 renal; 20 non-renal flares
- Bootsma: 156 patients; αdsDNA Ab levels measured monthly
- When **↑↑**: randomized to conventional Rx or addn 30 mg prednisone
- In 46: relapses in 20/24 v 2/22  p<0.001
- Bijl: in 36 patients: αdsDNA Ab levels measured monthly
- When ↑↑ in 10: MMF 2000 QD → no clinical relapses in 6 months

**TerBorg et al: A+R 1990; 33:634-43**

**Bootsma et al: Lancet 1995; 345:1595-9**

**Swaak et al: Ann Rh Ds 1986; 45:359-66**

**Bijl et al: Ann Rh Ds 2003: 62:534-9**

## Changes in dsDNA Ab; Complement 3 Levels

- LJP 394

- Placebo

**C3**

- % change

- % change

- % change in C3

- % change in C3

**	****                ****100 mg****	****50 mg****	****50 mg**

**0**

**10**

**20**

**30**

**40**

**50**

**0**

**10**

**20**

**30**

**40**

**50**

**Changes in ********dsDNA Ab; Complement 3 Levels**

**Study week**

## HRQOL Analysis

- All patients enrolled in LJP 394 phase 2/3 clinical trial 	who completed one baseline and follow-up SF-36
- Mean scores at endpoint and change scores in SF-36 	domains; PCS and MCS summary scores 	compared between active and placebo
- End of Induction [week 16] vs baseline (BL): 	    ITT [n=179] and ‘high affinity’ populations [n=157]
- Post vs Pre documented renal flare values;      +/- patients receiving high dose steroids and/or         	   cytotoxics [HDCC] prior to flare [n=37; n=30]

**Strand et al: Lupus 2003; 12:677-86**

## SF-36 Scores at Baseline Compared with Age, Gender Matched US Norms

**SF-36 Scores at Baseline Compared with ****Age, Gender Matched US Norms**

**Strand et al: Lupus 2003; 12:677-86**

## Mean Changes in SF-36 Domain Scores from Baseline to 16 Weeks [ITT]

**Mean Changes in SF-36 Domain Scores from ****Baseline to 16 Weeks [ITT]**

**Strand et al: Lupus 2003; 12:677-86**

## Mean Changes in SF-36 Domain Scores Pre and Post Renal Flare

**Strand et al: Lupus 2003; 12:677-86**

## Conclusions

- Patients with clinically stable SLE reported impaired HRQOL 	compared with age and gender matched US norms.
- During induction [16 weeks], SF-36 scores improved with 	active treatment, despite stable disease activity.
- Following a renal flare, patients receiving active treatment 	reported maintenance or improvement in HRQOL 	compared with deterioration in placebo; omitting patients 	who received HDCC prior to flare did not alter results.
- Differences in change scores in Role Emotional between 	treatment groups were replicated in all populations 	analyzed; are clinically meaningful, and may reflect 	changes in anti-dsDNA Ab levels.

**Strand et al: Lupus 2003; 12:677-86**

## Longitudinal Changes in anti dsDNA Abs in2 RCTs, Regardless of Treatment Group

**Longitudinal Changes in anti dsDNA Abs in****2 RCTs, Regardless of Treatment Group**

**Responder: ****≥****10% reduction in anti-dsDNA antibodies ****	****         in ****≥****2/3 of all determinations**

**Non -**
**responder**

- 30%
- 20%
- 10%
- 0
- -10%
- -20%
- -30%

- % change from BL

**Responder**

- Time (months)

## HRQOL Scores at Month 4 in «Responders» in 230 Patients with SLE

**PFI       ROLP****	****   PAIN****	****  GHP****	****   VITAL****	****     SOC****	****       ROLE****	****        MHI**

**Mean change scores**

## HRQOL Scores at Month 6 in «Responders» in 298 Patients with SLE

**Mean change scores**

**PFI       ROLP****	****   PAIN****	****  GHP****	****   VITAL****	****     SOC****	****       ROLE****	****        MHI**

## HRQOL Scores at Month 12 in «Responders» in 298 Patients with SLE

**Mean change scores**

**PFI       ROLP****	****   PAIN****	****  GHP****	****   VITAL****	****     SOC****	****       ROLE****	****        MHI**

## HRQOL Scores at Months 6 and 12 in «Responders» in 298 Patients with SLE

- Excluding 14 patients with renal flares ≤ 6 months do 	not change these results
- Excluding 41 patients with renal flares ≤ 12 months do 	not change these results
- Excludes use of high dose glucocorticoids and/or 	cyclophosphamide
- Are they clinically meaningful?
- → Analysis of “minimally clinically important differences”

## Mean Changes From Baseline in Patient Global VAS

**Week**

**Mean change +/-SEM**

## MCID in SF-36 Domains, PCS and MCS

- Correlation of change in 15 point scale by Guyatt et al:“In the past 3 months, has there been any change in your overall quality of life related to your lupus?”
- “a little better” = 6 on 15 point scale
- “a little worse” = 10
- Improvements → mean change scores
- Domains of SF-36: 6.7 – 11.4
- PCS and MCS: 3.4 – 3.9
- Worsening → mean change scores
- Domains of SF-36: +1.7 – -14.7
- PCS and MCS: -0.8 – -2.0

## Conclusions:

- Yes, it IS difficult to assess Outcomes in SLE
- Limited data derived from RCTs ― Yet to result in an ‘approved therapy’― Over a broad variety of promising interventions
- Patient Reported HRQOL is an IMPORTANT OUTCOME
- Reflects improvements in disease activity
- Deterioration due to use of high dose glucocorticoids 	and/or immunosuppressives
- Has correlated with longer term clinical outcomes
- May improve w/ sustained reductions in α dsDNA Abs
- Which are clinically meaningful** **