Clinical Trial Results:
Targeted Use of Placebo Effects Decreases Experimental Itch in Atopic Dermatitis Patients: A Randomized Controlled Trial
German: Nutzen des Placeboeffektes bei atopischer Dermatitis - Steigerung der pharmakologischen Wirkung bei Juckreiz durch Klassische Konditionierung und Erwartungsprozesse: Eine randomisierte kontrollierte Studie
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Summary
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EudraCT number |
2008-008474-31 |
Trial protocol |
DE |
Global end of trial date |
16 Mar 2014
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Sep 2022
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First version publication date |
04 Sep 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
PlacItch
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Additional study identifiers
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ISRCTN number |
ISRCTN12345678 | ||
US NCT number |
NCT02094287 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Charité - Universitätsmedizin Berlin
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Sponsor organisation address |
Charitéplatz 1, Berlin, Germany, 10117
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Public contact |
Prof. Margitta Worm, Charité - Universitätsmedizin Berlin,
Dpt. of Dermatology, Division of Allergy and Immunology, margitta.worm@charite.de
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Scientific contact |
Prof. Margitta Worm, Charité - Universitätsmedizin Berlin,
Dpt. of Dermatology, Division of Allergy and Immunology, margitta.worm@charite.de
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Mar 2014
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
16 Mar 2014
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Global end of trial reached? |
Yes
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Global end of trial date |
16 Mar 2014
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The study is initiated in the indication of atopic dermatitis to study the impact of placebo effects in the treatment of pruritus. Classical conditioning and expectation via instructions/anticipation maintain the effect of placebo.
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Protection of trial subjects |
All clinical tests (blood draw, skin prick test, questionnaires) and therapeutic interventions (infusion and instruction) were performed according to defined SOPs and clinical standards.
An patient insurance in accordance with the Medicines Act, Section 40, Paragraph 3 was provided for the probands for travel to the study center and for potential therapeutic side effects.
As no specific e.g. painful procedures were performed, no specific procedures were required.
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Background therapy |
All participants suffered from atopic dermatitis and received their individual background therapies. To explore the potential mediation role of expectation in driving itch re- duction (NRS 0–10; 0 = no itch, 10 = maximum itch) after conditioning, we performed a mediation analysis.24 The variable “conditioning” (yes/no) was treated as the independent variable , whereas the average delta score of the mean of “itch intensity ratings” of experimen- tal itch stimuli (NRS 0–10) from T1 baseline to T2, testing phase, and after intervention T2, was treated as dependent variable, “itch reduction baseline-T2” (criterion, Y). Expectations were assessed on day 2 (T2) at the beginning of the experiment (before infusion T2) by asking “Based on your current experience with our experimental itch stimulus, what itch relief on the NRS 0–10 do you expect from the following infusion?” Patients should provide two scores to indicate the expected itch relief. Reinforced expecta tion (average delta score between the current itch intensity rating and the predicted itch intensity rating with regard to experimental itch stimuli) was treated as the mediator (M) in mediation models. In this model, we calcu- lated the total effect of conditioning on itch reduction without mediator variable (c), the effect of the relationship between conditioning and itch reduction with the additional impact of expectation (c’), the direct effect of X to Mi (a), the direct effect of Mi to Y (b), and the indirect effect of X via Mi to Y (ab). IBM SPSS Statistics 21 software (IBM, Armonk, NY) was used in the per-protocol analysis. For the mediation analyses the macro “PROCESS” 3.5 by Andrew F. Hayes24 was used. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
03 Sep 2012
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 102
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Worldwide total number of subjects |
102
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EEA total number of subjects |
102
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
102
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
Recruitment via the in-house outpatients clinic | |||||||||||||||
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Pre-assignment
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Screening details |
Participants with a severity index (SCORing Atopic Dermatitis (SCORAD)) below 50 points, had no acute eczema on their forearms, were free of past or current psychiatric and neurological disorders, and received neither systemic treatments for skin diseases nor used topical treatments on their arms in the previous 4 and 2 weeks, respectively. | |||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | |||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Single blind | |||||||||||||||
Roles blinded |
Subject | |||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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OPEN-DRUG+INST | |||||||||||||||
Arm description |
openly infused dimetindene (drug) in full sight with information | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Dimetindene
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
15-minute infusion (dimetindene)
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Arm title
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OPEN-DRUG+INST+COND | |||||||||||||||
Arm description |
openly infused drug with an additional classical conditioning learning experience | |||||||||||||||
Arm type |
Experimental | |||||||||||||||
Investigational medicinal product name |
Dimetindene
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
15-minute infusion (dimetindene)
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Arm title
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HIDDEN-DRUG | |||||||||||||||
Arm description |
infused drug without any information or sight | |||||||||||||||
Arm type |
control group 1 | |||||||||||||||
Investigational medicinal product name |
Dimetindene
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
15-minute infusion (dimetindene)
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Arm title
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PLAC+INST+COND | |||||||||||||||
Arm description |
placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience | |||||||||||||||
Arm type |
control goup 2 | |||||||||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Injection/infusion
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Routes of administration |
Infusion
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Dosage and administration details |
15 minutes infusion of saline
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Baseline characteristics reporting groups
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Reporting group title |
OPEN-DRUG+INST
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Reporting group description |
openly infused dimetindene (drug) in full sight with information | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
OPEN-DRUG+INST+COND
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Reporting group description |
openly infused drug with an additional classical conditioning learning experience | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
HIDDEN-DRUG
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Reporting group description |
infused drug without any information or sight | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
PLAC+INST+COND
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Reporting group description |
placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
OPEN-DRUG+INST
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Reporting group description |
openly infused dimetindene (drug) in full sight with information | ||
Reporting group title |
OPEN-DRUG+INST+COND
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Reporting group description |
openly infused drug with an additional classical conditioning learning experience | ||
Reporting group title |
HIDDEN-DRUG
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Reporting group description |
infused drug without any information or sight | ||
Reporting group title |
PLAC+INST+COND
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Reporting group description |
placebo infusion (saline) declared as dimetindene and also experienced the conditioning experience | ||
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End point title |
Change of itch ratings | |||||||||||||||||||||||||||||||||||
End point description |
Primary treatment effects were estimated using generalized linear models: three repeated mea- sures analyses of variance (ANOVAs) with the within-subject factor “phase” (baseline, and testing phase T1 and T2) and between-subject factor “group” (HIDDEN-DRUG, OPEN-DRUG+INST, OPEN- DRUG+INST+COND, PLAC+INST+COND); η2 values were used as measures of effect sizes. Planned comparisons of the interaction ef- fects “phase * group” were conducted via orthogonal contrasts, with r as the effect size. Post hoc pairwise comparisons of treatment groups after the intervention were conducted via independent t-tests, with P = 0.025 as a Bonferroni-corrected criterion for significance. Difference scores between measurement phases (difference from baseline to T1, and difference from baseline to T2) were calculated and compared via a multivariate analysis of variance (MANOVA) with five a priori nonorthogonal contrasts on factor “group” to estimate the effects of placebo effects.
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End point type |
Primary
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End point timeframe |
from the baseline measurement to T1 and T2.
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Attachments |
Untitled (Filename: Chart_Itch intensity and wheal sizes at different time points.jpg) Untitled (Filename: Experimental substances_Figure_1_200124.tiff) Untitled (Filename: DISPOSITION OF PATIENTS_Figure_2_200124.tiff) |
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Statistical analysis title |
open drug + Inst vs. Hidden drug | |||||||||||||||||||||||||||||||||||
Comparison groups |
OPEN-DRUG+INST v HIDDEN-DRUG
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Number of subjects included in analysis |
50
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Analysis specification |
Post-hoc
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Analysis type |
superiority [1] | |||||||||||||||||||||||||||||||||||
P-value |
< 0.002 | |||||||||||||||||||||||||||||||||||
Method |
ANCOVA | |||||||||||||||||||||||||||||||||||
Parameter type |
Mean difference (final values) | |||||||||||||||||||||||||||||||||||
Confidence interval |
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Variability estimate |
Standard error of the mean
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| Notes [1] - three repeated measures analyses of variance (ANOVAs) with the within-subject factor “phase” (baseline, and testing phase T1 and T2) and between-subject factor “group” (HIDDEN-DRUG, OPEN-DRUG+INST, OPEN-DRUG+INST+COND, PLAC+INST+COND); η2 values were used as measures of effect sizes. |
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Statistical analysis title |
Plac+Inst+Cond vs. hidden drug | |||||||||||||||||||||||||||||||||||
Comparison groups |
PLAC+INST+COND v HIDDEN-DRUG
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Number of subjects included in analysis |
50
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Analysis specification |
Post-hoc
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Analysis type |
superiority | |||||||||||||||||||||||||||||||||||
P-value |
= 0 | |||||||||||||||||||||||||||||||||||
Method |
ANOVA | |||||||||||||||||||||||||||||||||||
Confidence interval |
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Statistical analysis title |
open drug+Inst+Cond vs. open drug +Inst | |||||||||||||||||||||||||||||||||||
Comparison groups |
OPEN-DRUG+INST+COND v OPEN-DRUG+INST
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Number of subjects included in analysis |
52
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | |||||||||||||||||||||||||||||||||||
P-value |
= 0.075 | |||||||||||||||||||||||||||||||||||
Method |
ANOVA | |||||||||||||||||||||||||||||||||||
Confidence interval |
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End point title |
Change of wheal size | |||||||||||||||||||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
from the baseline measurement to T1 and T2
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Attachments |
Itch intensity and wheal sizes at different times |
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| No statistical analyses for this end point | ||||||||||||||||||||||||||||||||||||
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Adverse events information [1]
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Timeframe for reporting adverse events |
from baseline to T2
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Assessment type |
Systematic | ||
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Dictionary used for adverse event reporting
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Dictionary name |
own | ||
Dictionary version |
1
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| Frequency threshold for reporting non-serious adverse events: 1% | |||
| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No AEs have been reported. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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31 Jul 2012 |
We submitted an BfArm-Amendment to add a relevant inclusion criterion, namely a baseline itch NRS value of ≥ 3. In addition, we increased the number of cases by 40 in this amendment because we wanted to do an additional investigation, namely microdialysis, in a small sample.
Extension of duration of study by two years. Resumption of recruitment (September 2012). |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The selection of study groups was clinically and feasibility oriented. The group PLAC+INST (placebo group without conditioning)were not used for ethical reasons. The histamine prick-test application without any treatment seemed us not justifiable. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/33894061 |
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