Clinical Trial Results:
A Phase II Open-label Multicenter Study to Assess the Efficacy and Safety of AFM13 in Patients with Relapsed or Refractory CD30-positive Peripheral T-cell Lymphoma or Transformed Mycosis Fungoides (REDIRECT).
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Summary
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EudraCT number |
2019-001003-20 |
Trial protocol |
ES DE PL IT |
Global end of trial date |
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Results information
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Results version number |
v1(current) |
This version publication date |
24 May 2023
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First version publication date |
24 May 2023
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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 |
AFM13-202
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04101331 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Affimed GmbH
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Sponsor organisation address |
Im Neuenheimer Feld 582, Heidelberg, Germany, 69120
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Public contact |
Clinical Operations, Affimed GmbH, +49 62216530770, trials@affimed.com
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Scientific contact |
Clinical Operations, Affimed GmbH, +49 62216530770, trials@affimed.com
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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 |
Interim
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Date of interim/final analysis |
13 Oct 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 May 2022
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Global end of trial reached? |
No
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General information about the trial
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Main objective of the trial |
To assess the antitumor activity of AFM13 by Independent Review Committee confirmed overall response rate (ORR)
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Protection of trial subjects |
Only eligible subjects that met all the study inclusion and none of the exclusion criteria could enter the study. Subjects could withdraw from the study at any time without stating a reason and without prejudice to further treatment. The investigator may have withdrawn a subject from the study and discontinued study drug and assessments at any time. The sponsor reserved the right to request withdrawal of a subject because of protocol violation or any other significant reason.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
30 Oct 2019
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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 |
Korea, Republic of: 13
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Country: Number of subjects enrolled |
Spain: 19
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Country: Number of subjects enrolled |
France: 7
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Country: Number of subjects enrolled |
Germany: 2
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Country: Number of subjects enrolled |
Italy: 12
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Country: Number of subjects enrolled |
United States: 16
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Country: Number of subjects enrolled |
Australia: 21
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Country: Number of subjects enrolled |
Turkey: 7
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Country: Number of subjects enrolled |
Russian Federation: 11
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Worldwide total number of subjects |
108
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EEA total number of subjects |
40
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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) |
58
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From 65 to 84 years |
49
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85 years and over |
1
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Recruitment
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Recruitment details |
This study was a Phase II open-label multicenter study to assess the efficacy and safety of AFM13 in subjects with relapsed or refractory CD30-positive peripheral T-cell lymphoma. | ||||||||||||||||||||
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Pre-assignment
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Screening details |
All the subjects were screened for CD30 expression. Investigators assessed the subjects, and they were enrolled in the study if they met all inclusion criteria and none of the exclusion criteria. | ||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||||||||
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Arms
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Arm title
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Cohort A | ||||||||||||||||||||
Arm description |
Subjects with Relapsed or Refractory CD30 positive Peripheral T-cell Lymphoma (PTCL). | ||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||
Investigational medicinal product name |
AFM13
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Intravenous AFM13 administered 200 milligram weekly until disease progression, unacceptable toxicity, Investigator discretion or withdrawal of consent.
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Baseline characteristics reporting groups
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Reporting group title |
Overall Study
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Subjects with Relapsed or Refractory CD30 positive Peripheral T-cell Lymphoma (PTCL). | ||
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End point title |
Overall Response Rate Assessed by Independent Review Committee Based on PET-CT [1] | ||||||||
End point description |
Overall response by Positron Emission Tomography-Computed Tomography (PET-CT) as defined by achieving complete response and/or partial response assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014).
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End point type |
Primary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months).
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| Notes [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point. Justification: Statistical analysis is included as a comment, no group comparison was made. |
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| Notes [2] - One side P-value for exact binomial test = 0.051. |
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| No statistical analyses for this end point | |||||||||
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End point title |
Complete Response Rate, Partial Response Rate and Overall Response Rate Assessed by Independent Review Committee Based on CT | ||||||||||||||
End point description |
Overall response by Computed Tomography (CT) as defined by achieving complete response and/or partial response assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months).
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| Notes [3] - One side P-value for exact binomial test = 0.537. |
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| No statistical analyses for this end point | |||||||||||||||
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End point title |
Duration of Overall Response Assessed by Independent Review Committee Based on PET-CT | ||||||||
End point description |
Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Positron Emission Tomography-Computed Tomography (PET-CT) by Independent Review Committee (IRC).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months).
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| No statistical analyses for this end point | |||||||||
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End point title |
Number of Subjects With Treatment Related Adverse Event | ||||||
End point description |
Number of subjects who had treatment (AFM13) related Adverse Events.
The safety set consisted of all subjects who received at least one dose of AFM13 and had at least one post-baseline safety assessment.
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End point type |
Secondary
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End point timeframe |
From the date of first treatment until the date of the last treatment + 37 days, up to 138 weeks.
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| No statistical analyses for this end point | |||||||
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End point title |
European Quality of Life 5-dimensional Pain/Discomfort Score (EQ-5D) | ||||||||||||||||||||||
End point description |
Quality of Life (QoL) as measured by the European QoL 5-dimensional questionnaire (EQ-5D) for Cohorts A. The EQ-5D comprises asks for the current health state in the five dimensions: mobility, self care, usual activities, pain/discomfort, and anxiety/depression. Pain/discomfort scores assessed based on questionnaire. The categories of the response offer three levels pain/discomfort score: "no pain or discomfort" (score of 1), "moderate pain or discomfort" (score of 2), and "extreme pain and discomfort" (score of 3). Scores are presented from baseline to each visit for Cohort A.
The full analysis set (FAS) followed the intent to treat principle and consisted of all subjects who received at least one dose of AFM13.
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End point type |
Secondary
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End point timeframe |
At baseline and final study visit, up to 138 weeks.
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| No statistical analyses for this end point | |||||||||||||||||||||||
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End point title |
European Quality of Life 5-dimensional Visual Analogue Scale Scores (EQ-5D) | ||||||||
End point description |
Quality of Life (QoL) as measured by the European Quality of Life 5-dimensional questionnaire (EQ-5D) for Cohorts A. Visual Analogue Scale scores assessed based on drawn scale from 0(worst imaginable state) to 100(best imaginable state). Subjects chose their health state on scale based on their situation by themselves.
The full analysis set (FAS) followed the intent to treat principle and consisted of all subjects who received at least one dose of AFM13.
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End point type |
Secondary
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End point timeframe |
From baseline until final study visit, up to 138 weeks.
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Response Rate Assessed by Investigator Based on PET-CT | ||||||||
End point description |
Overall response by Positron Emission Tomography-Computed Tomography (PET-CT) as defined by achieving complete response and/or partial response assessed by the investigator utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months).
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| Notes [4] - One side P-value for exact binomial test = 0.077 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Overall Response Rate Assessed by Investigator Based on CT | ||||||||
End point description |
Overall response by Computed Tomography (CT) as defined by achieving complete response and/or partial response assessed by the investigator utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months).
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| Notes [5] - One side P-value for exact binomial test = 0.159 |
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Overall Response Assessed by Independent Review Committee Based on CT | ||||||||
End point description |
Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Computed Tomography (CT) by Independent Review Committee (IRC).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months).
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| No statistical analyses for this end point | |||||||||
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End point title |
Complete Response Rate and Partial Response Rate Assessed by Independent Review Committee Based on PET-CT | ||||||||||||
End point description |
Complete response and/or partial response by Positron Emission Tomography-Computed Tomography (PET-CT) assessed by an Independent Review Committee (IRC) utilizing the modified Lugano Classification Revised Staging System for malignant lymphoma (Cheson, 2014).
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 28 months).
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Duration of Overall Response Assessed by Investigator Based on PET-CT | ||||||||
End point description |
Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Positron Emission Tomography-Computed Tomography (PET-CT) by the investigator.
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months).
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| No statistical analyses for this end point | |||||||||
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End point title |
Duration of Overall Response Assessed by Investigator Based on CT | ||||||||
End point description |
Duration of response (DOR) defined as the period from first Partial Response (PR) and Complete Response (CR) assessment till first assessment of progressive disease or death. Response assessed by Computed Tomography (CT) by the investigator.
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End point type |
Secondary
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End point timeframe |
Tumor assessment performed every 8 weeks for first 3 assessments, then every 12 weeks until documented disease progression (up to 26 months).
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Measured Concentration (Cmax) of AFM13 at Cycle 1/Day 1 | ||||||||
End point description |
Maximum measured concentration (Cmax) of the AFM13 in plasma.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1.
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| No statistical analyses for this end point | |||||||||
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End point title |
Maximum Measured Concentration (Cmax) of AFM13 at Cycle 1/Day 29 | ||||||||
End point description |
Maximum measured concentration (Cmax) of the AFM13 in plasma.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 29.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-Time Curve of AFM13 From 0 to Infinity (AUC 0-∞) at Cycle 1/Day 1 | ||||||||
End point description |
Area under concentration (AUC) versus time curve of the AFM13 in plasma over time interval from 0 extrapolated to infinity.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1.
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| No statistical analyses for this end point | |||||||||
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End point title |
Area Under the Concentration-Time Curve of AFM13 From 0 to Infinity (AUC 0-∞) at Cycle 1/Day 29 | ||||||||
End point description |
Area under concentration (AUC) versus time curve of the AFM13 in plasma over time interval from 0 extrapolated to infinity.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 29.
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution at Steady State (Vss) of AFM13 at Cycle 1/Day 1 | ||||||||
End point description |
Volume of distribution at steady state (Vss) of the AFM13.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1.
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| No statistical analyses for this end point | |||||||||
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End point title |
Volume of Distribution at Steady State (Vss) of AFM13 at Cycle 1/Day 29 | ||||||||
End point description |
Volume of distribution at steady state (Vss) of the AFM13.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 29.
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| No statistical analyses for this end point | |||||||||
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End point title |
The Terminal Half-life (t1/2) of AFM13 at Cycle 1/Day 1 | ||||||||
End point description |
The terminal half-life (t1/2) of the AFM13.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 1.
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| No statistical analyses for this end point | |||||||||
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End point title |
The Terminal Half-life (t1/2) of AFM13 at Cycle 1/Day 29 | ||||||||
End point description |
The terminal half-life (t1/2) of the AFM13.
The pharmacokinetic set (PK) consists of subjects who have at least received one dose of study drug and have at least one post dose PK measurement.
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End point type |
Secondary
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End point timeframe |
Predose and 1 hour after start of infusion, end of injection (EOI) and 1 hour, 2 hours, 3 hours, 24 hours and 48 hours after EOI on Cycle 1 Day 29.
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| No statistical analyses for this end point | |||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From the date of first treatment till the date of the last treatment + 37 days, up to 138 weeks.
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Adverse event reporting additional description |
The safety set consisted of all subjects who received at least one dose of AFM13 and had at least one post-baseline safety assessment.
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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 |
25.0
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Reporting groups
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Reporting group title |
Cohort A
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Reporting group description |
Subjects with Relapsed or Refractory CD30 positive Peripheral T-cell Lymphoma (PTCL). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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26 Mar 2019 |
Global Protocol Amendment 1, Final Version 2.0
Clarification on PTCL (Peripheral T-cell Lymphoma) and TMF (Transformed Mycosis Fungoides) definition to include Ber-H2 targeted IHC (Immunohistochemistry) using Ber-H2 targeted assay.
Photography for Cohort C was updated in different sections of the protocol to clarify that it referred to whole body photography.
Addition of the ALK (Anaplastic Lymphoma Kinase) status to be also performed centrally as well as information on the allowable age of tumor slides.
Update to the timeframe for blood sampling and ECG (Electrocardiogram) performance, cytokine testing time points and PK (Pharmocokinetics) sampling windows.
Definition of premedication timeframe and addition of timeframe information on assessment around EOI (End of Infusion). |
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07 Jun 2019 |
Global Protocol Amendment 2, Final Version 3.0 part 1/2
Redefinition of CD30 cut-offs for each cohort based on IHC validation levels.
Removal of 4 weeks confirmation criteria for Cohort A and B based on standard of care assessment criteria for PTCL (Peripheral T-cell Lymphoma) and update of study objectives to reflect the new requirement of 8 weeks for the definition of confirmed response for subjects in Cohort C.
Change of the secondary and exploratory objectives by inclusion of PET-CT (Positron emission tomography–computed tomography)-based ORR (Objective Response Rate) (secondary), and PFS (Progression-free Survival) and OS (Overall Survival) (exploratory); removal of the exploratory objective for the serum albumin levels.
Change of dosing schedule to weekly dosing for all treatment cycles based on FDA (Food and Drug Administration) feedback.
Specification on the allowed PTCL subtypes based on the FDA feedback and clarification on eligibility based on central testing with local results being allowed from sites with validated CD30 IHC assay only.
Updated measurable disease definition for Cohorts A and B to include FDG (Fluorodeoxyglucose) avid disease by PET.
Updated subject population definition and definition of intolerance and specified requirement for documentation of intolerance.
Updated laboratory functional parameters for inclusion/exclusion criteria so that PT (Preferred Term) and aPTT (Activated Partial Thromboplastin Time) were no longer specified as well as on exclusion of specific subtypes of lymphoma.
Reduced time from organ transplant prior study entry from 5 to 3 years.
Removal of the information that ventricular cardiovascular physiology was allowed.
Removal of impaired lung function as an exclusion criterion and change on Hepatitis B and C exclusion criteria language.
Removal of language that subjects with a CR (Complete Response) were allowed to have their AFM13 dosing held per FDA feedback. |
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07 Jun 2019 |
Global Protocol Amendment 2, Final Version 3.0 part 2/2
Updated definition of variable estimand based on the new requirement of 8 weeks for the definition of confirmed response for subjects in Cohort C.
Addition of a Pre-screening period to determine the suitability of subjects to enter the Screening Period based on their CD30 expression results and a requirement for subjects to sign a Pre-screening ICF (Informed Consent Form).
Addition of the modified Lugano Classification.
Replacement of mandatory premedication with recommended premedication and removal of NSAIDs (Non-steroidal Anti-inflammatory Drugs) as a part of the regimen.
Addition of new separate analyses of CR and PR independently in Section 8.5.1 and censoring rules for the DOR (Duration of Response) calculation in Section 8.6.1.2 of the protocol.
Addition of a plan to analyze the data if Cohort B had more than 4 responses, but Cohort A failed at stage 1 in Section 8.9 of the protocol.
Minor updates of the Schedule of Assessment (footnotes 2, 9-10, 12-13, 19-20).
Addition of serology and pathology testing to be performed by sites locally in Appendix D of the protocol.
Updated response criteria for PTCL to clarify that CT-based response will guide both the clinical decisions and the Overall Response assessment for subjects in Cohorts A and B. |
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02 Jul 2020 |
Global Protocol Amendment 3, Final Version 4.0 part 1/5
The overall rationale for this amendment was to update the protocol to introduce changes made to the premedication regimen for administration of AFM13, as well as the guidance for the management of AFM13 related IRRs and other AEs (Adverse Events).
Results of the recently completed study AFM13-103 were added to update current information about clinical studies conducted with AFM13.
PK considerations were updated based on results from previous AFM-13 studies that have shown that AUC0-∞ (Area Unver Curve) of at least 100,000 h*ng/mL (hours*nanogram/milligram) was important to increase the likelihood of achieving clinical benefit of AFM-13 treatment. Studies have also shown that lower albumin levels led to faster clearance, which impacted AUC. Modelling projections have shown that chosen AFM-13 dose for this study (200 milligram weekly) provided required exposure margin needed for clinical efficacy even in subjects with low albumin.
Language for endpoints was made more specific. Some of the secondary endpoints were moved to exploratory endpoints. Redundant language for some of the endpoints was removed. Of note, there was no impact on the overall scientific value of the study.
Considering the current COVID-19 pandemic situation, the sponsor recognized there could have been a situation where subject may have had to withdraw due to direct/indirect impact of COVID-19. A criterion for subject replacement was added for those subjects who dropped-out prior to their first post-baseline efficacy assessment. Also, impact of subjects dropping-out due to COVID-19 pandemic on sensitivity analysis was clarified. For this protocol, to cover the pandemic situation, up to 10 additional patients were allowed to be enrolled for Cohort A and 2 additional patients for Cohort C. |
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02 Jul 2020 |
Global Protocol Amendment 3, Final Version 4.0 part 2/5
Language in Section 3.1 (inclusion criteria) was amended to clarify the importance of central CD30 testing to determine eligibility in order to provide consistency in evaluation of CD30 expression in subjects across study sites.
Inclusion criterion # 5 was amended. The Sponsor recognized that the subject population for this study may have needed radiation therapy because of their disease condition. The criterion was added such that subjects who may have required radiation therapy for palliative intent to a single cutaneous lesion or single nodal lesion may have been enrolled in this study after agreement with the Sponsor.
Inclusion criterion #7 was amended. Alopecia is a common side effect of anti-cancer therapies. It was clarified that subjects who may have experienced alopecia (of any grade) with prior anti-cancer therapy were allowed to participate in the study.
Inclusion criterion #10 was amended. The Sponsor recognized that given the disease state under study in a R/R (Relapsed or Refractory) setting, there may have been subjects who had a compromised bone marrow but who could be reasonably supported medically in this regard. This text was added to provide clarification on when such may be considered for enrollment in the trial.
Exclusion criterion #6 was amended. Active Hepatitis B and Hepatitis C were broad exclusion criteria. In addition, the Sponsor recognized that there were some subjects with chronic hepatitis B who were effectively managed with antiviral prophylaxis to prevent reactivation in the setting of immunosuppression due to malignancy and the associated treatments. The language in this exclusion criteria was amended to reflect this understanding and provide further guidance on the eligibility or ineligibility of subjects who lived with this comorbidity. |
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02 Jul 2020 |
Global Protocol Amendment 3, Final Version 4.0 part 3/5
Details about process for subject enrollment were removed from protocol and a cross-reference was included to a separate document ‘Enrollment process’, which covered these details.
Published FDA guidance recognized that the COVID-19 pandemic may have affected the conduct of clinical trials. Special focus was therefore placed on the safety of trial subjects with modification of the study conduct accordingly. As such, in agreement with this guidance, the protocol was amended to include a criterion of withdrawing a subject from study upon a benefit-risk analysis, should that patient be directly or indirectly impacted due to pandemic. In addition, the Sponsor recognized that for some subjects it may have been clinically beneficial to transition to stem cell transplant once they had achieved durable response in the study. The amended language clarified that these subjects were to be withdrawn from the study.
Language on Pre-screening was amended to clarify that CD30 expression levels for all subjects were to be confirmed centrally to avoid any potential inter-site variance.
Text was updated to clarify that hepatitis serology was to be confirmed during screening period by laboratory tests, and HIV (Human Immunodeficiency Virus) serology was to be repeated only if the status was unknown.
Results from completed studies have shown that overall AFM-13 had low toxic potential as it related to adverse hematological events. However, evaluation of hematological parameters both pre-dose and now at the end of infusion may assist in the investigation of any potential hematological predictors of IRR (Infusion-related Reaction). In this regard, the Sponsor has updated the current protocol to clarify that hematological parameters were to be monitored closely during start of treatment in Cycle 1 Day 1, and results were to be collected and analyzed predose and end of infusion. |
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02 Jul 2020 |
Global Protocol Amendment 3, Final Version 4.0 part 4/5
Clarification on Exploratory Biomarker Flow Cytometry that samples could only be taken at sites that had the respective capabilities to cryopreserve them.
Clarification that CD30 positivity was to be evaluated centrally to determine study eligibility and that local IHC (Immunohistochemistry) results were not be used for this purpose. In addition, since this was trial in subjects with R/R disease, many of whom would have received multiple prior therapies, the protocol was also amended to state that biopsy samples older than 90 days prior to pre-screening were not allowed. This would better ensure that the CD30 expression at study entry was truly representative of the current status. In addition, it was further clarified that bone marrow biopsies were not accepted to enroll subjects in Cohorts A and B. The primary endpoint for these cohorts was to be assessed by CT scan, and similar to cutaneous lesions (cutaneous biopsies also not allowed to determine eligibility for Cohorts A and B), bone marrow responses were not assessed by CT scan.
To allow testing per local country specific requirements, text was updated to state that FSH (Follicle-stimulating Hormone) testing was allowed in blood or urine. However, it was clarified that if the results of urine test were not clear then the test was to be done with blood sample.
The sponsor recognized that due to current COVID-19 pandemic situation, there could have been operational challenges at different sites in different countries. It was recognized that a more intensive PK sampling schedule could be potentially more burdensome to trial subjects and site staff in the setting of this pandemic. As such, the criteria that mandated completing PK sampling in Group 1 prior to Group 2 were changed to state that Group 2 sampling (less intensive) could be commenced prior to completion of PK sampling in Group 1 (more intensive). This would not impact overall PK anal |
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02 Jul 2020 |
Global Protocol Amendment 3, Final Version 4.0 part 5/5
To improve the subjects’ tolerability to AFM13 while participating in the study and to maintain the planned dose intensity, which was assumed to improve antitumor activity, the sponsor issued a letter of amendment (LOA) mandating premedication with a regimen that included steroids. The LOA also included revisions for the management of IRR. The protocol was amended in alignment with the LOA including suggested revisions from the FDA.
AFM-13 infusion rate was specified in mg/hr instead of total infusion time to provide greater clarity, especially in the setting of infusion rate adjustments for IRRs, per FDA guidance.
Clarification that preventive hospitalizations due to COVID-19 situation were not to be categorized as SAEs (Serious Adverse Events).
Positive results for COVID-19 were considered an important medical situation and the criteria for immediate reporting were included in the protocol.
Guidance for Industry about sensitivity analysis was followed. Text was added to state that additional analyses might be needed due to current COVID-19 pandemic. This addition was in alignment to the following guidance: EMA/CHMP/ICH/436221/2017 Committee for Medicinal Products for Human Use ICH (International Council for Harmonisation) E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the guideline on statistical principles for clinical trials (17 February 2020).
Text clarified for the intent behind the interim analyses. Cohort C was not intended to have an interim analysis due to its size of 20 patients and the exploratory nature and the interim analysis was removed.
Additional subgroup analysis was introduced to evaluate the potentially combined Cohort A and B as subgroups at the final analysis.
Substantive changes made to Table 2 and Table 4 of the protocol, Version 3.0 (see Appendix 16.1.1). |
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29 Jun 2021 |
Global Protocol Amendment 4, Final Version 5.0
The overall rationale for this amendment was to update the protocol to change the primary form of assessment from CT scan to PET/CT based on updated NCCN (National Comprehensive Cancer Network) guidelines. Please note that Global Final Version 5.0 was signed but not distributed. |
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12 Jul 2021 |
Global Protocol Amendment 5, Final Version 6.0
The overall rationale for this amendment was to update the protocol to change the primary form of assessment from CT scan to PET/CT based on updated NCCN guidelines. This change was introduced in Version 5.0 from 29 June 2021. Prior to distribution of Version 5.0, additional changes for clarification of Inclusion Criteria #5 and #10 and an update of the shelf life as per the most recent IB update were added in Version 6.0 (12 July 2021).
Clarification on the premedication regimen language: The intent was to include at least an H1 antagonist with the option to also include an H2 antagonist.
Based on the recommendation of the Independent Safety Review Committee, the Sponsor provided more specific guidance for Investigators should their subjects have experienced treatment related adverse events. |
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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. | |||
| None reported | |||
