Clinical Trial Results:
A double-blind, placebo-controlled dose-escalation study of carbamylated monomeric tree pollen drops in patients with a history of allergic rhinoconjunctivitis.
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Summary
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EudraCT number |
2017-003063-34 |
Trial protocol |
DE |
Global end of trial date |
06 Nov 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
04 Aug 2021
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First version publication date |
04 Aug 2021
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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 |
GSDL_DE_17
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Lofarma Spa
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Sponsor organisation address |
viale cassala 40, Milan, Italy, 20143
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Public contact |
Coordinating Investigator, CRI - Clinical Research International Ltd. , 0049 1722056230, management@cri-ltd.de
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Scientific contact |
Coordinating Investigator, CRI - Clinical Research International Ltd. , 0049 1722056230, management@cri-ltd.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 |
06 Nov 2018
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
21 Jun 2018
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Global end of trial reached? |
Yes
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Global end of trial date |
06 Nov 2018
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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 primary objective of this trial is to assess the safety and clinical tolerability of Lais® Frühblüher sublingual drops in patients with birch pollen-induced allergic rhinoconjunctivitis.
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Protection of trial subjects |
To guarantee the patients’ safety during the treatment with Lais® Frühblüher, a Data Safety Monitoring Board (DSMB) was established, consisting of two independent experienced physicians in the field of allergy and one statistician. The DSMB was also supported by the Medical Monitor of the trial. The chairman of the DSMB checked the eCRF for information regarding treatment and (serious) AE reports, findings were discussed during weekly telephone conferences (during treatment phase), respectively.
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Background therapy |
The following rescue medication was provided; its use was restricted to the relief of local reactions induced by the investigational product and/or to relieve rhinoconjunctivitis symptoms: Fexofenadine tablets 120 mg | ||
Evidence for comparator |
placebo comparation | ||
Actual start date of recruitment |
18 Jan 2018
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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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: 37
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Worldwide total number of subjects |
37
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EEA total number of subjects |
37
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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) |
37
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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 |
Subjects were recruited from 5 German sites (6 sites planned but 5 initiated). Forty-eight patients were planned. Thirty-seven patients were screened. Of those, 21 were randomized. Two patients dropped-out (Physician Decision and Consent Withdrawal) First enrolment on January 18th, 2018. Last completed on June 21st, 2018. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Female or male patients aged 18 - 64 years. Having the diagnosis of allergy based on the following criteria: medical history of moderate to severe allergic rhinoconjunctivitis for birch pollen for at least 2 years, a positive skin prick test, specific IgE against birch pollen and positive response to conjunctival provocation test. | ||||||||||||||||||
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Period 1
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Period 1 title |
Escalation and maintenance (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Carer, Assessor | ||||||||||||||||||
Blinding implementation details |
During the dose escalation phase the investigational product doses were increased incrementally to reach the patient’s individual maximum tolerable dosage. The maintenance dose of 50,000 UA daily was self-administered by the patient from day 9 up to day 71.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Placebo solution was supplied in vials containing 9.0 mL of aqueous solutions containing sodium chloride, sodium hydrogen bicarbonate, glycerol and purified water having the same concentration as in the investigational product vial. | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral drops
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Routes of administration |
Sublingual use
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Dosage and administration details |
Same amounts of drops and same administration schedule of the IMP has been followed in order to maintain blinding condition.
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Arm title
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LAIS® Frühblüher sublingual drops | ||||||||||||||||||
Arm description |
LAIS® Frühblüher: At day 1: ultra-rush schedule of three doses to reach 17,000UA. From Day 2 to day 3: single dose of 10,000UA. At day 4: two doses to reach 40,000UA. From day 5 to Day 7: single dose of 25,00UA. Dose of 50,000 UA was self-administered daily by the patient from day 9 up to day 71. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
LAIS® Frühblüher sublingual drops
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Oral drops
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Routes of administration |
Sublingual use
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Dosage and administration details |
At day 1: ultra-rush schedule of three doses to reach 17,000UA. From Day 2 to day 3: single dose of 10,000UA. At day 4: two doses to reach 40,000UA. From day 5 to Day 7: single dose of 25,00UA. Dose of 50,000 UA was self-administered daily by the patient from day 9 up to day 71. A dose adjustment of the investigational product was foreseen for safety reasons under particular conditions and following specific rules.
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| Notes [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Altogether, 37 patients were screened during the study. 15 patients did not meet the inclusion/non-inclusion criteria and one patient withdrew consent after the screening visit. Therefore, 21 patients were randomised and received study medication. 6 patients were treated with placebo and 15 patients with Lais® Frühblüher. |
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo solution was supplied in vials containing 9.0 mL of aqueous solutions containing sodium chloride, sodium hydrogen bicarbonate, glycerol and purified water having the same concentration as in the investigational product vial. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
LAIS® Frühblüher sublingual drops
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Reporting group description |
LAIS® Frühblüher: At day 1: ultra-rush schedule of three doses to reach 17,000UA. From Day 2 to day 3: single dose of 10,000UA. At day 4: two doses to reach 40,000UA. From day 5 to Day 7: single dose of 25,00UA. Dose of 50,000 UA was self-administered daily by the patient from day 9 up to day 71. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Intention-To-Treat (ITT) efficacy population (ITT-set) included all randomised patients who received at least one dose of study treatment and had a record of primary safety measures on at least one day of the observation period.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Per Protocol population includes all evaluable patients in the ITT population without any major protocol deviations interfering with the evaluation of the secondary endpoint.
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Subject analysis set title |
S-Set
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Subject analysis set type |
Safety analysis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The Safety population includes all randomised patients
who received at least one dose of study treatment
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo solution was supplied in vials containing 9.0 mL of aqueous solutions containing sodium chloride, sodium hydrogen bicarbonate, glycerol and purified water having the same concentration as in the investigational product vial. | ||
Reporting group title |
LAIS® Frühblüher sublingual drops
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Reporting group description |
LAIS® Frühblüher: At day 1: ultra-rush schedule of three doses to reach 17,000UA. From Day 2 to day 3: single dose of 10,000UA. At day 4: two doses to reach 40,000UA. From day 5 to Day 7: single dose of 25,00UA. Dose of 50,000 UA was self-administered daily by the patient from day 9 up to day 71. | ||
Subject analysis set title |
ITT
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
The Intention-To-Treat (ITT) efficacy population (ITT-set) included all randomised patients who received at least one dose of study treatment and had a record of primary safety measures on at least one day of the observation period.
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Subject analysis set title |
PP
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The Per Protocol population includes all evaluable patients in the ITT population without any major protocol deviations interfering with the evaluation of the secondary endpoint.
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Subject analysis set title |
S-Set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
The Safety population includes all randomised patients
who received at least one dose of study treatment
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End point title |
Safety and clinical tolerability | ||||||||||||
End point description |
The safety and clinical tolerability of Lais® Frühblüher was assessed by the following variables:
• Solicited adverse events including local reactions at the administration site
(oropharyngeal and gastrointestinal symptoms) and systemic allergic reactions
after investigational medicinal product administration.
• Unsolicited adverse events
• Proportion of patients who reached the maximum dose
• Use of rescue medication during treatment phase
• Physical examinations and vital signs
• Laboratory investigations on blood samples (blood count, renal and liver
function parameters)
• Pulmonary functions for asthmatic patients
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End point type |
Primary
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End point timeframe |
from January 18th, 2018 to June 21st , 2018
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Statistical analysis title |
Local and Systemic Reaction | ||||||||||||
Statistical analysis description |
Local reactions and systemic allergic reactions after medicinal product administration were considered as Solicited Adverse Events. Local reactions during updosing visits were documented in two patients. In total, six systemic allergic reactions with two symptoms have been reported by one actively treated patient (6.7% of actively treated patients). No systemic allergic reaction grade II, III or IV according to AWMF classification was reported.
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Comparison groups |
Placebo v LAIS® Frühblüher sublingual drops
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [1] | ||||||||||||
P-value |
= 0.5212 | ||||||||||||
Method |
t-test, 2-sided | ||||||||||||
Parameter type |
Odds ratio (OR) | ||||||||||||
Point estimate |
2.7576
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
2.12 | ||||||||||||
upper limit |
61.16 | ||||||||||||
Variability estimate |
Standard deviation
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| Notes [1] - Local reactions and systemic allergic reactions after study drug administration |
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End point title |
Efficacy | |||||||||||||||
End point description |
Analysis of the secondary safety endpoints unsolicited AEs, vital sign (Summary statistics for vital signs (n, mean, SD, median, minimum, maximum, percentiles, and 95% confidence intervals) and physical examinations, safety laboratory variables, pulmonary function and use of rescue medication during treatment phase was performed in the safety population.
Moreover, Immunogenicuty and Conjunctival provocation test.
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End point type |
Secondary
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End point timeframe |
from January 18th, 2018 to June 21st , 2018
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Statistical analysis title |
Immunogenicity IgE | |||||||||||||||
Statistical analysis description |
Immunogenicity analyses:
Exploratory variables corresponding to the immunogenicity endpoints (at V1 and V6) compared the two treatment groups (ITT-set) regarding production of birch pollen specific IgE, (at V1 and V6 and change from V1). All patients had to have a birch pollen specific IgE serum level ≥ 0.7 kU/L at screening visit V1 to meet the inclusion criteria.
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Comparison groups |
LAIS® Frühblüher sublingual drops v Placebo
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | |||||||||||||||
P-value |
= 0.032 [3] | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Confidence interval |
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| Notes [2] - At V1, mean concentration of specific IgE was higher in the placebo group (22.322 kU/L) than in the active group (19.971 kU/L). In the placebo group, the mean concentration increased at V6 to 26.153 kU/L, while in the verum group increased at V6 to 45.369 kU/L. Placebo ΔV6-V1 was 3.832 kU/L and active ΔV6-V1 was 25.398 kU/L.This increase resulted in a statistical significance p=0.001. The mean CAP class increased from 3.33 to 3.60 in placebo group and from 3.50to 4.21 in active group. [3] - Placebo ΔV6-V1 was 3.832 kU/L and Lais® Frühblüher ΔV6-V1 was 25.398 kU/L. |
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Statistical analysis title |
Immunogenicity IgA | |||||||||||||||
Statistical analysis description |
Immunogenicity analyses:
Exploratory variables corresponding to the immunogenicity endpoints (at V1 and V6) compared the two treatment groups (ITT-set) regarding: Production of birch pollen specific IgA (at V1 and V6 and
change from V1).
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Comparison groups |
LAIS® Frühblüher sublingual drops v Placebo
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [4] | |||||||||||||||
P-value |
= 0.157 | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Confidence interval |
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| Notes [4] - At V1, the mean concentration of sIgA was 1.080 mg/L in the placebo and 1.013 mg/L in the verum group. At V6, sIgA concentrations were identical in both groups with 1.000 mg/L, showing no relevant changes in sIgA levels from V1 to V6 (Placebo ΔV6-V1: -0.080, Lais® Frühblüher ΔV6-V1: -0.013, Figure 11-4). |
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Statistical analysis title |
Immunogenicity IgG4 | |||||||||||||||
Statistical analysis description |
Exploratory variables corresponding to the immunogenicity endpoints (at V1 and V6) compared the two treatment groups (ITT-set) regarding: Production of birch pollen specific IgG4 (at V1 and V6 and change from V1).
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Comparison groups |
LAIS® Frühblüher sublingual drops v Placebo
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [5] | |||||||||||||||
P-value |
= 0.482 [6] | |||||||||||||||
Method |
t-test, 1-sided | |||||||||||||||
Confidence interval |
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| Notes [5] - At V1, the mean concentration of sIgA was 1.080 mg/L in the placebo and 1.013 mg/L in the verum group. At V6, sIgA concentrations were identical in both groups with 1.000 mg/L, showing no relevant changes in sIgA levels from V1 to V6 (Placebo ΔV6-V1: -0.080, Lais® Frühblüher ΔV6-V1: -0.013). [6] - no relevant changes in sIgA levels from V1 to V6 : Placebo ΔV6-V1: -0.080, Lais® Frühblüher ΔV6-V1: -0.013 |
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Statistical analysis title |
Immunogenicity ratio | |||||||||||||||
Statistical analysis description |
Exploratory variables corresponding to the immunogenicity endpoints (at V1 and V6) compared the two treatment groups (ITT-set) regarding: IgG4/IgE ratio. Summary statistics (n, mean, SD, median, minimum, maximum, percentiles, and 95% confidence intervals) were presented for each group.
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Comparison groups |
Placebo v LAIS® Frühblüher sublingual drops
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Number of subjects included in analysis |
21
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Analysis specification |
Post-hoc
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Analysis type |
other [7] | |||||||||||||||
P-value |
= 0.741 [8] | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Confidence interval |
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| Notes [7] - At V1, the sIgG4/sIgE ratio was 0.110 in the placebo and 0.033 in the Lais® Frühblüher group. At V6, the ratio was nearly unchanged in the placebo group (0.112) while in the actively treated group, the ratio decreased by 41% to 0.0196. In the placebo group, [8] - ΔV6-V1 was 0.0019 and -0.0136 in the actively treated group |
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Statistical analysis title |
CTP (Reactivuty Score) | |||||||||||||||
Statistical analysis description |
This score was used to analyse the improvement of CPT-reactivity between V1 and
V6 and to compare the improvement between actively treated and placebo patients
using the following scoring system:
-2 = Worsen. of two allergen coc. steps
-1 = Worsen. of one allergen coc. steps
0 = No change
+1 = Improvement of one allergen coc. steps
+2 = Improvement of two allergen coc. steps
+3 = Improvement of three allergen coc. steps
+4 = Improvement of four allergen coc. steps.
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Comparison groups |
LAIS® Frühblüher sublingual drops v Placebo
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [9] | |||||||||||||||
P-value |
= 0.45 | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Confidence interval |
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| Notes [9] - The mean CPT reactivity score (RS) at V1 was lower in the placebo group than in the Verum group. However, due to the high standard deviations in both groups, this difference may not be meaningful. ΔV6-V1 in the placebo group was 0.00 and -0.23 in the actively treated group. The change in the actively treated group showed a trend towards improvement (p=0.083). The change from V1 to V6 is higher in the verum group than in the placebo group. |
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Statistical analysis title |
CPT (Composite Score) | |||||||||||||||
Statistical analysis description |
The composite score (CS) is a combination of all severity scores at a corresponding visit and was calculated for each patient at each visit .
The clinical effects of the IMP were assessed using the Composite Score (CS) (Astvatsatourov et al. 2014). The CS was calculated for each patient at each visit. Summary statistics (n, mean, SD, median, minimum, maximum, percentiles, and 95% confidence intervals) were presented for each group.
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Comparison groups |
LAIS® Frühblüher sublingual drops v Placebo
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Number of subjects included in analysis |
21
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Analysis specification |
Pre-specified
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Analysis type |
other [10] | |||||||||||||||
P-value |
= 0.0314 [11] | |||||||||||||||
Method |
t-test, 2-sided | |||||||||||||||
Confidence interval |
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| Notes [10] - The mean CS of the placebo group was only slightly reduced (by 7.5%) from the screening visit (0.40) to the last visit (0.37), while the CS of the Lais® Frühblüher group decreased by 19.5% from the screening visit (0.41) to the last visit (0.19). This reduction (ΔV6-V1: -0.076) was statistically significant (p=0.038). A statistical significance was not shown for the placebo group. Despite the small number of patients, the CPT data indicates clinical efficacy of Lais® Frühblüher drops. [11] - The changes of each parameter from V1 to V6/V6b were calculated and compared between the placebo and the actively treated group. |
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Adverse events information
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Timeframe for reporting adverse events |
The AE were collected during the entire duration ot the treatment, both in escalation and in mantainance phase
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Adverse event reporting additional description |
Local reactions and systemic allergic reactions after study drug administration were defined as solicited adverse events. These solicited AEs were used to assess the primary endpoint, the safety and clinical tolerability of Lais® Frühblüher treatment. Also unsolicited AEs were collected
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
21.0
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Overall, one unsolicited TEAE was observed in one placebo patient (16.7%) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Lais® Frühblüher
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 Apr 2018 |
Version 3.0 : implementation of the optional study visit V6b |
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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. | |||
| a limitation has been the small number of subject included that didn't permit the efficacy explorative evaluation | |||
