Use of a Standardized Documentation System

P S Y C H O P H A R M A C O L O G Y Btj

Use of a Standardized Documentation System (BLIPS/BDP) in the Conduct of a Multicenter International Trial Comparing Fluvoxamine, Imipramine, and Placebo Giovanni B. Cassano, M.D.,^ Luciano Conti, M.D.,' Gabriele Massimetti, M.D.,^ Francesco Mengali, M.D.,^ Jenifer S. Waekelin, M.D.,^ancl Jerome Levine,

Introduction W h e n i n 1978 D u p h a r B V , H o l l a n d , d e c i d ed to o r g a n i z e a m u l t i c e n t e r i n t e r n a t i o n a l clinical t r i a l w i t h the a i m o f assessing efficacy a n d safety o f a n e w selective s e r o t o n i n e r g i c antidepressant c o m p o u n d , f l u v o x a m i n e m a l eate ( F U V O X ) , the B L I P S / B D P system ( B i o metrie L a b o r a t o r y I n f o r m a t i o n P r o c e s s i n g System/Data Bank for Psychopharmacology), used at the C e n t e r f o r C l i n i c a l Psychopharmacology Data Documentation ( C C P D D ) o f the Institute o f C l i n i c a l P s y c h i a try o f the U n i v e r s i t y o f Pisa, a p p e a r e d to p r o vide the necessary u n d e r l y i n g s t r u c t u r e f o r the study by o f f e r i n g a n efficient s t a n d a r d data d o c u m e n t a t i o n system. T h e o r g a n i z a t i o n a l m o d e l that was used f o r the study p r o v i d e d that t h e c o m p a n y w o u l d m a i n t a i n t h e i r usuai r o l e i n t h e s e l e c t i o n o f sites, m o n i t o r i n g a n d c o l l e c t i n g data, a n d s u p p l y i n g drugs to t h e sites. T h e r o l e o f t h e Pisa center i n c l u d e d c o n s u l t a t i o n o n t h e design o f the study, c h o i c e o f the r a t i n g scales, and provision o f a standardized documentation a n d analysis system, n a m e l y the B L I P S /

^Institute of Clinical Psychiatry, University of P i s a . P i s a . Italy. Department of Clinical R e s e a r c h , Duphar B V , W e e s p , T h e Nemertands. ' K K. ^Maryland Psychiatric R e s e a r c h Center, University of M a r y land. Bammofe. M D 21228.

T h e c o m p a n y p r o v i d e d t h e r a w originai d a t a c o l l e c t e d f r o m t h e investigators to the C C P D D . T h e y o r g a n i z e d several meetings w i t h p r i n c i p a l investigators i n w h i c h the Pisa c e n t e r p a r t i c i p a t e d , b u t t h e Pisa c e n t e r had n o a d d i t i o n a l contacts w i t h t h e p a r t i c i p a t i n g investigators. T h e a d v a n t a g e s o f this o r g a n i z a t i o n a l model i n c l u d e : a) o p e n c h o i c e o f sites a n d investig a t o r s (investigators d o n o t n e e d to b e l o n g to a p r e v i o u s l y o r g a n i z e d g r o u p ) ; b) t h e company plays its usuai r o l e w i t h r e g a r d to site sel e c t i o n a n d m o n i t o r i n g ; a n d c) t h e B L I P S / B D P d o c u m e n t a t i o n a n d analysis system does n o t r e q u i r e t h e use o f special p u r p o s e (trial specific) r a t i n g scales b u t o n l y t h e use o f a standardized identification block. Therefore, w i d e l y used r a t i n g scales c a n b e u t i l i z e d by i n v e s t i g a t o r s w i t h o u t t h e necessity o f special training, only checks o f interrater reliability. T h i s results i n a very cost-effective f l e x i b l e m o d e l w h i c h , as we w i l l show,, is sufficiently sensitive to establish efficacy a n d safety.

Material and Methods T h e p l a n n e d " D u p h a r " t r i a l was a n international multicenter, double-blind, prospectively r a n d o m i z e d c l i n i c a l t r i a l a i m e d at c o m p a r i n g t h e a n t i d e p r e s s a n t a c t i v i t y a n d safety o f F L U V O X w i t h that o f i m i p r a m i n e ( I M I ) and placebo ( P B O ) in i n - or outpatients aged o v e r 18 years a n d s u f f e r i n g f r o m a m a j o r depressive illness ( a c c o r d i n g to t h e D S M - I I I defmition). I n i t i a l l y , t h e r e w e r e 12 p a r t i c i p a t i n g c e n ters, 7 i n N o r t h A m e r i c a a n d 5 i n E u r o p e ( T a b l e 1). F L U V O X a n d I M I , i n u n i t doses o f 50 m g , a n d P B O , i n indistinguishable capsules, w e r e a d m i n i s t e r e d a c c o r d i n g t o a f i x e d f l e x i b l e d o s a g e s c h e d u l e : o n e capsule t h e first day, t w o capsules t h e s e c o n d d a y , a n d t h r e e capsules f r o m t h e t h i r d to t h e s e v e n t h d a y . A f t e r t h e first week t h e dosage c o u l d b e a d j u s t e d , a c c o r d i n g to c l i n i c a l j u d g m e n t , f r o m a m i n i m u m o f o n e to a m a x i m u m o f s i x capsules p e r d a y a n d a d m i n i s t e r e d , w h e r e possi-

TABLE1

Participating Centers and Data Available for Analyses Patients for the Intent to Treat Analysis*

Patients Enrolied Locations

Principal Investigators

No.

No.

Patients for the Efficacy Analysis " (No.)

item, USA

Goldstein'^

101

87

86.1

59

58.4

New York. U S A

Farkas^

52

44

84.6

28

53.9

Ottawa, C a n a d a

Lapierre"^

63

60

95.2

45

71.4

Montreal, C a n a d a

Anantrr^

31

29

93.6

24

77.4

t^ondon. England

Paykel/Sirelig'

46

London, England eal, C a n a d a I. France

Paykel/Norton^

45

91

100.0

83

91.2

Amin*=

91

89

97.8

75

82.4

Darcourt'

52

48

92.3

43

82.7

481

448

93.1

357

74.2

Totais on, U S A

Caranza»

3

Houston, U S A

Caranza*

16

Turin. Italy

Ravizza*

Pisa, Italy

Cassano/Conti'

3 45

•f'fttents w»th at least two evaiuations on drug. •Pttients with at least 14 days medication and not dropped out after the Uth day t^cause of possible study drug-related concurrent signs and symptoms or for reasons unreteted to study group. «Outpatients. nnpatients. •Study stopped after only a few patients enrolied; data not included in the analysis. flacetxs-controlled study conducted under the same protocol; data not included in the analysis.

ble, three times a day. N o o t h e r p s y c h o t r o p i c medications w e r e a l l o w e d w i t h the e x c e p t i o n o f c h l o r a l h y d r a t e o r f l u r a z e p a m , as h y p n o t ics, only w h e n this was u n a v o i d a b l e . Patients w i t h an e s t a b l i s h e d d i a g n o s i s o f major depressive illness a n d w i t h a s c o r e o f at ìeast 15 o n the first 17 items o f the H a m i l t o n R a t i n g Scale for D e p r e s s i o n ( H A M - D ) at the end o f the p r e t r e a t m e n t p e r i o d , a n d not p r e cluded by the e x c l u s i o n c r i t e r i a ( c h i l d b e a r i n g potential o r p r e g n a n t w o m e n ; a n t i d e p r e s s a n t therapy in the past 2 weeks; e l e c t r o c o n v u l s i v e therapy w i t h i n the last m o n t h ; d e p r e s s i v e symptoms s e c o n d a r y to o t h e r p s y c h i a t r i c i l l ness; d e p e n d e n c e u p o n licit o r i l l i c i t d r u g s ; serious o r g a n i c diseases; n e e d f o r c o n c u r r e n t medications w h i c h c o u l d i n t e r a c t w i t h the study drugs o r o b s c u r e t h e i r effects; a n d p a tients u n w i l l i n g o r u n a b l e to c o o p e r a t e i n the study) were i n c l u d e d i n the t r i a l .

Assessment instruments were mostly the s t a n d a r d r a t i n g i n s t r u m e n t s o f the B L I P S / B D P a n d the assessments w e r e d o n e o n e n t r y , at the last p r e t r e a t m e n t day, a n d w e e k l y t h e r e a f t e r ( T a b l e 2). T h e m a i n a i m o f this p a p e r is to d e m o n strate the u t i l i t y o f the o r g a n i z a t i o n a l m o d e l f o r this k i n d o f study. Because o f that, we w i l l c o n s i d e r o n l y the A d u l t P e r s o n a l D a t a I n v e n t o r y ( A P D I ) f o r the d e m o g r a p h i c d a t a , t h e P a t i e n t T e r m i n a t i o n R e c o r d ( P T R ) f o r the t r i a l d a t a , the H A M - D a n d the C l i n i c a l G l o b al I m p r e s s i o n Scale ( C G I ) f o r efficacy d a t a , a n d the D o s a g e a n d T r e a t m e n t E m e r g e n t S y m p t o m s Scale ( D O T E S ) a n d T r e a t m e n t W r i t e - i n S c a l e ( T W I S ) f o r safety d a t a .

A f t e r a p r e t r e a t m e n t p e r i o d o f 3 to 7 days, d u r i n g w h i c h o n e capsule o f P B O i n d i s t i n guishable f r o m the t r e a t m e n t capsules was given, patients r e c e i v e d d r u g s f o r u p to 28 days. F o r the N o r t h A m e r i c a n c e n t e r s , the treatment p e r i o d was e x t e n d e d to 4 2 days. Analyses p r e s e n t e d b e r e are f o c u s e d o n 2 8 day data i n o r d e r to u t i l i z e b o t h E u r o p e a n and N o r t h A m e r i c a n data.

O f the 12 p a r t i c i p a t i n g centers, o n l y 8 furn i s h e d sufficient data f o r analyses ( T a b l e 2). T h r e e c e n t e r s ( N o s . 3, 4, a n d 7) s t u d i e d i n p a tients; a l i the o t h e r s s t u d i e d o u t p a t i e n t s . T w o N o r t h A m e r i c a n centers ( N o s . 8a a n d 8b) a n d o n e E u r o p e a n c e n t e r ( N o . 9) bave b e e n e x c l u d e d f r o m the analyses because o f the s m a l l n u m b e r o f patients e n r o l i e d . D u e to a d e l a y i n o b t a i n i n g p e r m i s s i o n to c o n d u c t t h e t r i a l

Results

I

54

PSYCHOPHARMACOLOGY

BULLETIN

TABLE 2

Assessment Instruments and Schedule On Entry

Past Pretreatment Day

Day 7

Day 14

Day 21

Day 28»

X X X X X

X X X X X

X X X X X

X X X X X

X X X X X

X X X X X X

X X X X

X X X X X X X

X X X X

X X X X X X X X X

so) i n

the

X X X X X X

Adult Personal Data Inventory (APDI)'» Prior Medication R e c o r d ( P M R ) Clinical Examination Clinical Global Impression (CGI)'* BrIef Psychiatric Rating S c a l e ( B P R S ) Hamilton Rating S c a l e for D epression (HAM-D)'' Self-Report S y m p t o m Inventory (SCL-90) Self-Rating D ep r es s i o n S c a l e (SDS) Dosage R e c o r d and Treatment Emergent Symptom S c a l e (DOTES)*»" T E S S Write-in (TWIS)''= Concurrent Medication Vital S ig n s Hematology/Biochemistry Drug LeveI Electrocardiograph Patient Termination R e c o r d (PTR)*» Investigator S u m m a r y

X X X

X

•Or if the patient leaves the study before day 28. ''Assessment instruments utilized in the present analysis. =And at each change of dosage or if new important symptoms shouid emerge.

f r o m the I t a l i a n a u t h o r i t i e s , the Pisa c e n t e r ( N o . 10) c o n d u c t e d a separate P B O - c o n t r o l l e d t r i a l u n d e r the same p r o t o c o l ; the Pisa data are not i n c l u d e d i n these analyses. O f the 481 e n r o l i e d patients, 4 4 8 h a d at least two e v a l u a t i o n s d u r i n g the d r u g i n t a k e p e r i o d ( T a b l e 1) a n d b a v e b e e n i n c l u d e d i n the A P D I , P T R , a n d D O T E S analyses. T h e d i s t r i b u t i o n o f the patients a c c o r d i n g to t h e i r m a j o r d e m o g r a p h i c c h a r a c t e r i s t i c s ( A P D I ) — a g e , sex, m a r i t a i status, p r i o r treatments, significant m e d i c a i c o n d i t i o n s , a n d previous hospitalizations—is approximately the same i n the t h r e e t r e a t m e n t g r o u p s . T h e l e s s - t h a n - l - y e a r d u r a t i o n o f the a c t u a l e p i -

sode is less (but n o t s i g n i f i c a n t l y P B O g r o u p ( T a b l e 3).

D a t a f r o m the P T R ( T a b l e 4) p r o v i d e significant d i f f e r e n c e s a m o n g the t h r e e g r o u p s . T h e d u r a t i o n o f t r e a t m e n t is a p p r o x i m a t e l y the same, b u t the r e a s o n s f o r p r e m a t u r e term i n a t i o n d i f f e r s i g n i f i c a n t l y b e t w e e n active d r u g s a n d P B O . A s c a n be e x p e c t e d , i n the P B O g r o u p p r e m a t u r e i n t e r r u p t i o n s f o r ineffectiveness are r e l a t i v e l y m o r e f r e q u e n t t h a n i n the t w o a c t i v e d r u g g r o u p s , w h e r e a s the o p p o s i t e is t r u e f o r the a d v e r s e r e a c t i o n s . T h e r e w e r e n o d i f f e r e n c e s a m o n g the g r o u p s i n the n u m b e r o f p a t i e n t s r e q u i r i n g h y p n o t ics, but a t r e n d i n s u g g e s t i n g m a i n l y that patients o n a c t i v e d r u g s r e q u i r e d m o r e gastro-

TABLE 3

Demographic Summary (APDI) Variables

Total Number of Patients: Age: M e a n ( ± S D ) Min. - M a x . Sex: Remale Maritai Status: Ever Married Prior Treatments: Any Prior Treatment Duration of Present E p i s o d e : L e s s than 1 year Significant Medicai Conditions: Any Condition Previous Hospitalization: None

I

FLUVOX

IMI

PBO

161 42.7 ( ± 1 3 . 7 ) 19-70 99(61.5%) 131 (81.4%) 102(63.4%) 108(67.1%) 20(12.4%) 117(72.7%)

153 41.3 ( ± 1 3 . 8 ) 10-70 92(60.1%) 104(68.0%) 107(70.0%) 103(67.3%) 11 (7.7%) 108 (70.6%)

149 42.1 ( ± 1 1 . 8 ) 21 - 68 95 (63.8%) 119(79.9%) 99(66.4%) 111(74.5%) 21 (14.1%) 104 (69.8%)

55

TABLE 4

Patient Termination Summary (PTR) — 4 Weeks' Treatment T < ^ Days in Study: M e a n ( ^ SD) fif^mature Termination* fcieffectiveness Improvement Adverse Reactions Unrelated to Treatment Completed 28 Days of Treatment: Amitdary Medications: Gastrojntestinal Preparations Hypnotics Given the choice, would you continue on this study medication (1) Mean ( ± S D ) "

FLUVOX

IMI

PBO

23.3 ( ± 7 . 6 )

23.9 ( ± 7 . 3 )

24.5 ( ± 6 . 4 )

12 2 19 21 102 (63.4%)

10 3 17 17 104 (63.0%)

26 1 5 17 100 (67.1%)

24(14.9%) 77 (47.8%)

21 (13.7%) 72 (47.1%)

9 (6.0%) 63 (42.3%)

2.24 ( ± 1 . 4 )

2.11 ( ± 1 . 5 )

1.74(±1.5)

•Chi-SQuare= 19.08. 0 05 *• Analyas of vanance regular: p< 0.05 n) Scaie Potnts; 0 - Definitely No 1 - inclined to Say No 2 » Undecided 3 = Inclined to Say Yes 4 Oefiniteiy Yes

intestina! p r e p a r a t i o n . T o the q u e s t i o n i " G i v en the c h o i c e , w o u l d y o u c o n t i n u e o n this study m e d i c a t i o n ? " the i n v e s t i g a t o r s ' a n s w e r is significantly in favor o f the t w o active drugs. T h e m e a n daily dosage o f the t h r e e treatments is s i m i l a r i n b o t h the week-by-week analysis a n d in the o v e r a l l t r e a t m e n t p e r i o d . M a x i m u m dosage is r e a c h e d i n the t h i r d week ( T a b l e 5). T h e most f r e q u e n t side effect (rated at least m o d e r a t e ) o b s e r v e d i n the F L U V O X g r o u p is "nausea." " D r y m o u t h , " "sweating," a n d "dizziness" are m o r e frequent in the I M I g r o u p ( T a b l e 6). T h e s e p r e l i m i n a r y f m d i n g s a l l o w us to disc r i m i n a t e b e t w e e n the t w o active c o m p o u n d s and P B O a n d , o n the basis o f side effects, to differentiate F L U V O X f r o m I M I . TABLE 5

Mean Daily Dosage Fluvoxamine

Week 1 Week 2 Week 3 Week 4 Ali Periods

Mg

(No of Capsules)

115.03 157.16 177.47 134.55 144.95

2.3 3.1 3.5 2.7 2.9

Placebo

Imipramine Mg

(No of Capsules)

Mg

(No. of Capsules)

118.09 161.48 176.56 144.20 149.06

2.4 3.2 3.5 2.9 3.0

124.83 184.17 203.70 153.52 166.02

2.5 3.7 4.1 3.1 3.3

A t this p o i n t , r a t h e r t h a n d e s c r i b e f u r t h e r the s t a n d a r d o u t p u t o f the B L I P S / B D P syst e m , we w o u l d r a t h e r e m p h a s i z e the f l e x i b i l i ty a n d p o t e n t i a l for r a p i d l y a n d easily l o o k i n g at the d a t a i n d i f f e r e n t ways. W e w i l l d e m o n strate the possibilities o f f e r e d by the B L I P S / B D P system i n h a n d l i n g a n d a n a l y z i n g the p o o l e d data o f a large multicenter trial. T h e m a j o r statistica! p r o c e d u r e e m p l o y e d in the f o l l o w i n g analyses was a two-way a n a l y TABLE 6

Emergent Signs and Symptoms (Moderate and Severe) FLUVOXAMINE

IMI

PBO

No . of Patients

161

153

149

Dry mouth Nausea Somnolence Insomnia Constipation Headache Sweating Dizziness Agitation Anorexia Tremor Hyperkinesia Hypokinesia Hypotension Manie reaction

8 29 17 15 13 14 7 2 8 6 4 4 8 1 1

31 9 15 10 11 6 13 15 8 4 7 4 2 6 4

10 6 2 6 5 10 4 4 3 4 2 4 1 3 2

56

P S Y C H O P H A R M A C O L O G Y BULLETIN

TABLE 7

t e m , it is possible to p e r f o r m t h e t w o types o f analysis, o n e i m m e d i a t e l y after t h e o t h e r , by s i m p l y g i v i n g t h e c o m p u t e r t h e d i f f e r e n t selection criteria.

CGI — Severity of Illness: Results of Two-Way Covariance Analysis Intent-to-Treat Analysis

Efficacy Analysis

Percent of Improvement

Score* Inrtial Final

Score* Initial Final

Percent of Improvement

Fluvoxamine

4.41

3.26

26.1

4.46

2.99

33.0

lmipranr>ine

4.47

3.29

26.4

4.47

3.08

31.1

Placebo

4.51

3.62

19.7

4.54

3.53

22.3**

•Standardized «cores. ••Analys«s of covar.ance: FLUVOX PBO>pp P - p---0 05 l > P - p < 0 05

-

T A B L E 11

Stratification by Treatment Setting: HAM-D Retardation Factor Score* Initial

Final

Improvement

Total Sample

F 1 P

2.38 2.20 2.29

1.23 1.26 1.62

48.3 42.7 29.3"

Inpatients

F 1 P

2.77 2.54 2.63

1.18 .98 1.44

57.4 61.4 45.2

Outpatients

F 1 P

2.18 2.05 2.14

1.26 1 38 1.69

42.2 32.7 21.0

2.65 2.12

1.20 1.45

54.7 31.7—

Total Sample: Inpatients Outpatients

F = Fluvoxamine, I = Imipramine: P = Placebo •Adjusted scores. "Covariance analysis: F > P - p< 0 05 l > P - p - 0.05 •"Covariance analysis: Inpatients>Outpatients - p