Desmopressin Response In the Treatment of Primary Nocturnal Enuresis DRIP

1
Desmopressin Response In
the Treatment of
Primary Nocturnal Enuresis (DRIP)

• A multi-national study of oral desmopressin
  treatment in children
• aged 5 to 15 years with
  Primary Nocturnal Enuresis

2
Notes for affiliates rationale for slide set

• This slide set has been developed to present
  highlights of the recently completed Desmopressin
  Response In the Treatment of Primary Nocturnal
  Enuresis (DRIP) study
• Internal use The slide set is suitable for all
  internal use
• External use The slide set will be suitable for
  training physicians and also for presenting to
  their peers in roll out meetings and workshops

3
Notes for affiliates references and supporting
materials

• Initial abstracts accepted for presentation as
  posters at the forthcoming 37th Annual Meeting of
  the International Continence Society, Rotterdam
• Lottmann H et al. Desmopressin Response In the
  treatment of Primary Nocturnal Enuresis DRIP
  An open-label, multi-national study
• Evans J and Lottmann H. Desmopressin Response In
  the treatment of Primary Nocturnal Enuresis in
  the United Kingdom DRIP UK An open-label,
  randomised comparative study of oral desmopressin
  versus enuresis alarm
• Abstracts published as proceedings from this
  meeting
• Full publications are being prepared for
  publication in global peer-reviewed journals by
  the end of the year
• Epidemiology and treatment strategies
• The DRIP slide set should be used in conjunction
  with the slide set disseminated following the
  Barcelona meeting Managing Enuresis Latest
  Trends in the Treatment of Bedwetting (November
  2006), for further information on epidemiology
  and treatment options in PNE

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Notes for affiliates key messages supported by
the slides

• This is the largest clinical study of PNE
  conducted in 744 patients across four countries
  including Canada, France, Germany and the UK
• Long-term desmopressin treatment is effective in
  previously untreated children with PNE
• Age and nocturnal diuresis are predictive factors
  for response
• Patients who seek help at a later age can still
  achieve a good response
• Partial response is important for patients
  progress is rewardingand motivating
• High patient compliance is associated with
  greater response (and vice versa)
• Long-term desmopressin treatment is well
  tolerated in children with PNE
• Many patients deserve a long-term treatment
• The safety profile of desmopressin is similar
  irrespective of age and can be used in patients
  from the age of 5 years

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5
Desmopressin Response In
the Treatment of
Primary Nocturnal Enuresis (DRIP)

• A multi-national study of oral desmopressin
  treatment in children
• aged 5 to 15 years with
  Primary Nocturnal Enuresis

6
Primary Nocturnal Enuresis (PNE) definition and
prevalence

• PNE is defined as
• Bedwetting in children 5 years old who have
  never been dry for an
  uninterrupted period of 6 months1
• PNE affects 610 of children aged 7 years25
• If untreated, PNE persists into adolescence for
  up to 3 of children67

1. Neveus T et al. J Urol 200617631424 2.
Chiozza ML et al. Br J Urol 199881(Suppl
3)869 3. Hellstrom AL et al. Eur J Pediatr
19901494347 4. Hialmas K et al. J Urol
2004171254561 5. Kanaheshwari Y. J Pediatr
Child Health 20033911823 6. Abrams P et al.
3rd International Consultation on Incontinence
200581150 7. Moilanen I et al. Br J Urol
199881(Suppl 3)947
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PNE impact

• Social and emotional issues1,2
• Anxiety
• Low self-esteem
• Withdrawal from socialisation
• Children rate PNE as the third most traumatic
  event after parental divorce and parental
  fighting3

1. Schulpen TW. Acta Paediatr 1997869814 2.
Butler RJ. Scand J Urol Nephrol 20013516976

3.
Van Tijen NM et al. Br J Urol 199881(Suppl
3)989
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PNE emotional impact

• I was a bedwetter, whichis miserable at
  boardingschool. Clunes the piddler
• Kids tease you for anything
• Its good to get all your major humiliations out
  of the way early in life
• Martin Clunes

Martin Clunes is a UK-based actor and permission
should be obtained before using his image.
Ideally permission to use the image of a local
celebrity in your own market should be sought.
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PNE pathophysiology

• Multifactorial, but
• Nocturnal polyuria is main cause, in up to 70 of
  cases1,2
• Nocturnal polyuria leads to over production of
  urine at night volume exceeds capacity of the
  bladder
• Nocturnal polyuria is caused by abnormal
  circadian rhythm of antidiuretic hormone AVP
  secretion3,4

1. Aceto G et al. J Urol 2004171256770 2.
Abrams P et al. 2nd International Consultation on
Incontinence 200248151
3. Fergusson DM et
al. Pediatrics 19867888490 4. Rittig S et al.
Am J Physiol 1989256F66471
AVP, arginine vasopressin
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PNE treatment options
Two main options
Medical treatment
Conditioning devices
eg desmopressin
eg enuresis alarms
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Desmopressin

• Synthetic analogue of antidiuretic hormone AVP1
• V2-receptor specific
• Devoid of pressor activity associated with AVP
  stimulation of V1-receptors
• Mimics the antidiurectic action of AVP1
• Longer duration of action and more potent than
  vasopressin
• Reduces nocturnal urine output
• Well tolerated with few side effects24
• Endorsed by the International Consultation on
  Incontinence5
• First-line treatment for PNE of polyuric origin
  (Level 1, Grade A)

Nørgaard JP et al. Neurourology and Urodynamics
2007 0018 (epub ahead of print). Reprinted with
permission of Wiley-Liss, Inc., a subsidiary of
John Wiley Sons, Inc. Adapted from Figure 1,
page 8 of Robertson GL and Norgaard JP, BJU
International 2002907-10 with permission of
Blackwell Publishing Ltd.
1. Brink HS et al. Clin Nephrol 19944295101
2. Hjalmas K et al. Br J Urol 1998827049 3.
Janknegt RA et al. J Urol 199715751374. Vande
Walle J et al. BJU Int 2006976039 5. Nijman R
et al. Incontinence Volume 2management
20059651058
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DRIP study overview

• Largest clinical study of desmopressin
• Children aged 515 years
• Period of treatment 6 months
• 744 patients from 86 centres in
• Canada
• France
• Germany
• UK

Patients in the UK were randomised to either
desmopressin or an enuresis alarm, while patients
in the rest of the study used desmopressin
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DRIP objectives

• Main objective
• To evaluate the overall response to, and
  tolerability of, oral desmopressin in children
  with PNE
• Secondary objective
• Identification of factors that might be useful as
  clinical predictors of a good
  response to treatment

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Patients

• Inclusion criteria
• Previously untreated or treatment naïve
• Aged 515 years
  (615 years in France)
• 6 wet nights during the
  2-week screening period

• Exclusion criteria
• Diurnal symptoms (eg urgency, frequency, and/or
  day wetting)
• Encopresis
• Renal or central diabetes insipidus with AVP
  deficiency
• Known urinary tract infection (past month)
• Fluid retention and/or cardiac
  failure
• Clinically significant diseases
• Medication which could interfere
  with the study or with desmopressin

Patients previously unsuccessfully treated with
desmopressin or other medications over 1 year
ago, and/or for less than 4 weeks, were
considered to be treatment-naïve
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DRIP study overview
Screening period 2 weeks 2 days, no treatment
Run-in period 2 weeks, 0.2 mg desmopressin
Treatment period 3 months, 0.2 or 0.4 mg
(Germany 6 weeks)
Treatment period (Canada only) 3 months, 0.4 or
0.6 mg
Washout period 2 weeks
Wet
Dry
Treatment period 3 months, 0.2 or 0.4 mg, Canada
0.4 or 0.6 mg (Germany 6 weeks)
Follow-up 16 months
Follow-up 16 months
UK alarm arm excluded
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Evaluations

• Efficacy assessments
• Primary
• 1) Response to desmopressin percentage reduction
  in mean number of wet nights/week
  from screening to the last 2 weeks of treatment
• Secondary
• 2) Mean number of wet nights/week for each period
• 3) Percentage of patients remaining dry after the
  wash-out period
• 4) Possible predictive factors for response
  (country, gender, age, maximal voiding volume,
  nocturnal diuresis, family history of PNE)
• Safety assessments
• Adverse events
• Body mass index

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Response categories
As defined by ICCS guidelines (Neveus et al. J
Urol 2006176(1)31424)
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Patient distribution
Screened 936
Enrolled 744 (79)
Withdrew 273 (37)
Completed 471 (63)
Percentage based on number of screened children
all other percentages are based on number of
enrolled patients
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Baseline demographics of patients (n744)
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Patients family history and
baseline enuresis characteristics (n744)

• Bedwetting characteristics
• Nocturnal diuresis
• median 0.319 mL/min
• range 0.001.386 mL/min
• Maximal voiding volume
• median 179.0 mL
• range 301100 mL
• Wet nights/week
• median 6
• range 27

• Family history of PNE percentage of patients

Missing data
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Treatment response is consistent across countries
70
Overall (n744)
63
60
60
59
UK (n192)
57
60
Canada (n205)
50
Germany (n213)
France (n134)
40
Percentage of patients
28
30
25
24
22
21
18
17
17
20
16
15
10
0
90 reduction
50 to lt90 reduction
lt50 reduction
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Long-term desmopressin treatment is effective
Response status at end of treatment
70
60
90 reduction in wet nights
50
5089 reduction in wet nights
40
Percentage of patients
17
59
30
20
24
10
0
50 reduction in wet nights per week
lt50 reduction in wet nights per week
The lt50 reduction group includes 23 patients
(3) who did not provide an evaluable response
23
Age and nocturnal diuresis predict response
24
Older children who seek help can still achieve a
good response
Number of wet nights/week at screening and end of
treatment by age group
8
At screening
EOT
7
6
5
Mean number (and SD) of wet nights/week
4
3
2
1
0
Overall (n744)
58years (n423)
911 years (n204)
12 years (n117)
25
Higher patient compliance is associated with
a greater response
Percentage of patients achieving 50 reduction
in wet nights per week by compliance
50
46.6
46.2
40
27.8
30
25.0
Percentage of patients
20
14.5
10
0
gt75 of tablets taken
Taken as instructed
Unknown compliance
lt50 of tablets taken
5075 of tablets taken
26
Patients benefit from long-term treatment
Response status by time interval
50
Dry at washout
90 reduction
50

89

reduction
40
9
13
30
Percentage of patients
11
6
20
24
21
19
10
0
Run-in treatment period
1st treatment period
2nd treatment period
Canadian 2nd run-in data excluded
27
Partial response is important

• Medication is rewarding
• The ultimate goal is to become dry, and children
  with PNE who are
  treated are more likely to stop wetting than
  those who are not
  treated
• Improvement motivates children to continue
  treatment
• Therapy needs to be continued for some time
  (months or years), so it is important that
  children experience improvement and feel
  motivated to continue treatment

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Desmopressin a good long-term
safety profile (1)

• 5 (38/744) of patients suffered treatment
  emergent adverse events (TEAEs), interpreted as
  related to study medication
• No drug-related TEAEs were considered serious
  most common complaints were headache and
  abdominal pain
• 7 serious adverse events, unrelated to drug
• Safety profile similar in all age groups

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Desmopressin a good long-term
safety profile (2)
Most common TEAEs (2)

• Only 5 of patients experienced TEAEs that were
  considered to be related to study medication,
  the most common being abdominal pain not
  otherwise specified (4/744, 1), upper abdominal
  pain (6/744, 1) and headache (8/744, 1)

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Summary

• Long-term desmopressin treatment is effective in
  nocturnal enuresis
• Age and nocturnal diuresis predict response
• Patients who seek help at a later age can still
  achieve a good response with desmopressin
• Higher compliance is associated with a greater
  response
• Partial response is common and may precede full
  response
• Many patients need long-term treatment
• Long-term desmopressin treatment is well
  tolerated
• Safety profile of desmopressin is similar
  irrespective of age