Clinical Trial Results:
A Clinical Study of ColoAd1 Administered by Sub-Acute Fractionated Intravenous Injection: Dose Escalation in Metastatic Epithelial Solid Tumours and Randomised Controlled Trial in Metastatic Colorectal Cancer
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Summary
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EudraCT number |
2012-001067-79 |
Trial protocol |
ES GB BE |
Global end of trial date |
29 Apr 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
11 May 2017
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First version publication date |
11 May 2017
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Other versions |
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Summary report(s) |
Summary of secondary endpoints |
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 |
ColoAd1-1001
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02028442 | ||
WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
PsiOxus Therapeutics Ltd
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Sponsor organisation address |
154B Brook Drive, Abingdon, United Kingdom, OX14 4SD
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Public contact |
Chief Medical Officer, PsiOxus Therapeutics Ltd, +44 (0)1235835328, HMJ@Psioxus.com
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Scientific contact |
Chief Medical Officer, PsiOxus Therapeutics Ltd, +44 (0)1235835328, HMJ@Psioxus.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 |
Final
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Date of interim/final analysis |
29 Apr 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
29 Apr 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
29 Apr 2016
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Phase I:
To evaluate the safety and tolerability of ColoAd1, when administered by sub-acute fractionated intravenous (IV) injection to subjects with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists
To determine the maximally-tolerated dose and/or maximum-feasible dose of ColoAd1 when administered by sub-acute fractionated IV injection to subjects with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists, and to recommend a dose for phase II studies.
Phase Ib:
To select a suitable schedule and dose for repeat cycle IV administration of ColoAd1 in subjects with metastatic colorectal (mCRC) cancer or urothelial cell cancer
Phase II: Not performed
To evaluate progression free survival in subjects with mCRC when ColoAd1 is administered IV as intensification of first line chemotherapy compared with first line chemotherapy alone
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Protection of trial subjects |
The trial was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonisation guidelines on Good Clinical Practice and other applicable regulatory requirements. All personal data collected during the study were managed by the Investigator and study staff with adequate precautions to ensure confidentiality of those data, and in accordance with national local laws and regulations on personal data protection.
This was a first-in-human study and measures were put in place to minimise risk to subjects:
• Subjects with immunosuppressed background were excluded and concurrent administration of immunosupressants was prohibited
• Subjects were eligible only when they had recovered to ≤Grade 1 from toxicities (excluding alopecia) of previous systemic treatment or radiotherapy.
• Only subjects with a good performance status (ECOG of 0 or 1) and those with adequate bone marrow, liver and renal functions and normal international normalised ratio were eligible for the study
• The Phase I part of the study was conducted by experienced Investigators in Phase I units with experience of novel therapeutic agents in Phase I studies
• All subjects in the Phase I Dose Escalation Stage were hospitalised until Day 6 to allow close monitoring during and after all administrations of ColoAd1
• Although the risk of virus shedding was thought to be minimal due to the highly attenuated nature of the virus subjects were excluded unless alternate living arrangements could be made for household contacts that were pregnant, <1year old or had severe immunosuppression
• A Clinical Events Committee, which included an independent oncologist, reviewed the safety data from each cohort of the Phase I part of the study to determine the dose for the next cohort. Additionally a Data and Safety Monitoring Committee constituted according to regulatory guidelines reviewed the safety data at the end of the Phase I part of the study
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Background therapy |
None | ||
Evidence for comparator |
The Phase II part of the study which involved comparison of sequential treatment with ColoAd1 and chemotherapy with chemotherapy alone was not performed | ||
Actual start date of recruitment |
20 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 |
Spain: 32
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Country: Number of subjects enrolled |
Belgium: 29
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Worldwide total number of subjects |
61
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EEA total number of subjects |
61
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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) |
40
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From 65 to 84 years |
21
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85 years and over |
0
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Recruitment
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Recruitment details |
Phase I: Dose escalation using 3+3 design. 1st subject consented in Belgium 20SEP12. 1st subject in Spain 14JAN13. Then dose expansion group 9 subjects & repeat cycle group 6 subjects. Phase Ib: Comparison weekly & 3 weekly dosing schedules. 1st subject 27OCT14. Study terminated after 6 evaluable subjects each group. Sites: 3 Belgium 3 Spain 0 UK | ||||||||||||||||
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Pre-assignment
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Screening details |
Phase 1: 50 Screened, 37 enrolled & dosed. 13 screen failures: 8 inadequate renal function, 2 inadequate hepatic function, 2 compliance, 1 ECOG score Phase I: 31 screened, 24 enrolled & dosed. 7 screen failures: 5 inadequate renal function one also with inadequate bone marrow function, 2 other excluded medical conditions | ||||||||||||||||
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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 | ||||||||||||||||
Blinding implementation details |
Open label in both Phase I and Phase Ib.
CT scans read centrally by blinded independent assessor.
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Arms
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Arm title
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Overall study | ||||||||||||||||
Arm description |
Phase 1: 3+3 design evaluating different doses, total of 7 cohorts (Cohorts 1-7) followed by dose expansion cohort (Cohort 10) and a repeat cycle cohort (Cohort 8). No Cohort 9. Phase Ib: weekly versus 3-weekly dose schedule comparison, total 5 cohorts | ||||||||||||||||
Arm type |
Experimental | ||||||||||||||||
Investigational medicinal product name |
ColoAd1
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Investigational medicinal product code |
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Other name |
INN: Enadenotucirev
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Pharmaceutical forms |
Injection
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Routes of administration |
Intravenous use
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Dosage and administration details |
Cohort 1: 1x10*10 viral particles (vp) by IV infusion over 5 minutes
Cohort 2: 1x10*11 vp by IV infusion over 5 minutes
Cohort 3:1x10*12 vp by IV infusion over 5 minutes*
Cohort 4: 1x10*13 vp by IV infusion over 5 minutes*
Cohort 5: 3x10*12 vp by IV infusion over 5 minutes
Cohort 6: 3x10*12 vp by IV infusion over 20 minutes*
Cohort 7: 6x10*12 vp by IV infusion over 40 minutes
In all cohorts three infusions given separated by 48 hours on Days 1, 3 and 5 (one cycle)
* one subject retreated at a later date with one cycle
Cohort 8: 6x10*12 vp by IV infusion over 40 minutes Days 1, 3 and 5 every 3 weeks for 3 or 4 cycles
Cohort 10: 6x10*12 vp by IV infusion over 40 minutes single cycle, 3 subjects retreated
Phase Ib: 1 x 10*12, 3 x 10*12 or 6 x 10*12 vp on Days 1, 3 and 5 every 3 weeks for up to 6 cycles or 3 x 10*12 or 6 x 10*12 vp on Days 1, 3, 5 then 8 then weekly for up to 6 3 week cycles by IV infusion
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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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Subject analysis sets
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Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Safety analysis set included all subjects who received at least a partial dose
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End points reporting groups
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Reporting group title |
Overall study
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Reporting group description |
Phase 1: 3+3 design evaluating different doses, total of 7 cohorts (Cohorts 1-7) followed by dose expansion cohort (Cohort 10) and a repeat cycle cohort (Cohort 8). No Cohort 9. Phase Ib: weekly versus 3-weekly dose schedule comparison, total 5 cohorts | ||
Subject analysis set title |
Safety analysis set
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Subject analysis set type |
Safety analysis | ||
Subject analysis set description |
Safety analysis set included all subjects who received at least a partial dose
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End point title |
Safety and tolerability - adverse events, laboratory data and vital signs [1] | ||||||||||||
End point description |
Tables attached of all adverse events occurring in 5% or more of subjects overall also broken down by dose groups: < 1 x 10*12, 1-3 x 10*12 and > 3x 10*12 viral particles.
Also attached are a summary of adverse events, laboratory data and vital signs.
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End point type |
Primary
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End point timeframe |
From time of first dose until 56 days after last dose for cohorts 1-7 and 10 in Phase I and from first dose until 28 days after last dose for cohort 8 in Phase I and Phase Ib
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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: No statistical analysis performed. Only descriptive summaries were prepared due to the small numbers in each cohort of this exploratory study. Continuous variables were summarised using the number of observations, mean, standard deviation (SD), median, minimum, and maximum. Categorical variables were summarised using number of observations, frequency and percentages of patients. |
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Attachments |
Untitled (Filename: Adverse events in 5% or more of subjects.pdf) Untitled (Filename: Summary of adverse events.pdf) Untitled (Filename: Summary of laboratory test data.pdf) Untitled (Filename: Summary of vital signs data.pdf) |
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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 |
Phase I cohorts 1-7 and 10 from first dose until 56 days after last dose
Phase 1 cohort 8 and Phase Ib from first dose until 28 days after last dose
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Adverse event reporting additional description |
See attachment for full list of adverse events in ≥ 5% subjects.
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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 |
19.1
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Reporting groups
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Reporting group title |
Overall study
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Reporting group description |
Data from the two phases of study integrated. Due to small numbers of subjects in dose groups, adverse events summarised for those in ≥5% subjects overall. Deaths in survival FU included. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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Date |
Amendment |
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01 Aug 2012 |
Amendment implemented before the start of study to incorporate requested during Competent Authority review to clarify and adequately define criteria for dose limiting toxicities, the period of adverse event follow up and timepoints for pharmacokinetic blood sampling during Phase I |
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22 Jan 2013 |
To clarify requirements and procedures for retreatment of subjects with ColoAd1, to clarify the eligibility criterion relating to renal function, to clarify how disease related toxicities should be considered, when assessing dose limiting toxicities and to clarify adverse event and serious adverse event reporting exemptions.
To change the Medical Monitor from Dr Hamina Patel to Dr John Beadle
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18 Apr 2013 |
To update the dose escalation schedule and to introduce the possibility of extending the duration of infusion of ColoAd1 based on a review of the literature and the safety data generated at this point due to the occurrence of dose limiting toxicities at the 1 x 10*13 vp dose and possible correlation with pharmacokinetic and cytokine profile data
To add assessments of viral kinetics, viral shedding and cytokines in the Phase I Dose Expansion Cohort
To clarify the roles of the Clinical Events Committee and Data and Safety Monitoring Committee for the choice of the doses to be used for the Phase I Dose Expansion Cohort, the Phase II Dose Feasibility and the randomised Phase II stages
To change the Medical Monitor from Dr John Beadle to Dr Christine Wilkinson Blanc
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22 Sep 2013 |
To introduce the Repeat Cycle Cohort (Cohort 8)
To update the eligibility criteria and timing for retreatment
To update the inclusion criterion relating to adequate renal function to define absence of clinically significant haematuria on urinalysis as dipstick <2+ instead of dipstick <1+ or <3 red blood cells per high-power field on microscopic analysis and absence of clinically significant proteinuria on urinalysis as dipstick <2+ instead of dipstick <1+ or <150 mg per day on 24 hour urine collection or urine protein-creatinine ratio <30 mg/mmol creatinine. The original criterion had been set to reflect the potential renal tropism of Ad11, this criterion was relaxed as no renal adverse events or urinalysis changes had been seen at this point
To update the inclusion criterion relating to the maximum number of prior systemic therapies for advanced disease allowed for colorectal cancer subjects selected for the Phase I Dose Expansion Cohort. Treatment of subjects with tumours that are EGFR positive usually includes an anti-EGFR therapy either combined with other therapeutic agents or alone. The inclusion criterion originally allowed three prior systemic therapies and was updated to allow four prior systemic therapies if one of them was an anti-EGFR single agent or combined to a previously administered chemotherapy regimen
To allow flexibility in the pre-medication with ibuprofen
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11 Aug 2014 |
To introduce Phase Ib to expand the repeat dosing investigation to compare a weekly schedule with the 3 weekly schedule included previously performed in a homogeneous population of subjects with mCRC or UCC
To update the inclusion criteria relating to adequate renal function to define absence of clinically significant haematuria on urinalysis as dipstick ≤2+ instead of dipstick <2+ and absence of clinically significant proteinuria on urinalysis as dipstick ≤2+ instead of dipstick <2+ to match the usual definition of these criteria in oncology as there had been no renal adverse effects in the subjects treated at that point
To allow for the collection of tissue samples from unplanned surgery biopsies performed within 90 days of first administration of ColoAd1 as analysis of collected tissue, tumour or normal tissue may allow for further understanding of the delivery and expression of ColoAd1
To relax the contact exclusions and the precautions to be taken with household contacts based upon shedding data from the Phase I Dose Escalation and Dose Expansion Stages
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14 Nov 2014 |
To include the following mandatory laboratory safety assessments prior to the Day 8 and Day 15 infusions of ColoAd1 in the weekly schedule which had been omitted in error in the previous version and to introduce optional assessments on Day 3 and Day 5 of Cycle 2 onwards in the 3 weekly schedule:
-Cycle 1: mandatory assessments on Day 8 and Day 15 for all subjects
-Further cycles: mandatory assessments on Day 8 and Day 15 for the first 12 subjects and optional assessments based on investigators clinical judgment on days 8 and 15 for subsequent subjects
To specify the dose adjustments to be performed if DLTs were observed in Phase Ib
To introduce the possibility of a dose reduction under the 3 weekly schedule as well as under the weekly schedule if the dose recommended for Phase II was not tolerated under the weekly schedule
To update the primary objective for Phase Ib to specify that it is to determine both a schedule and dose for further studies with repeat cycle administration
To assess a small cohort of subjects at the dose immediately below the dose recommended for Phase II (three subjects under each schedule) to provide information to support intra-subject dose reductions and future combination studies
To further relax the eligibility criteria relating to adequate renal function by removing haematuria and proteinuria as measured on dipstick urinalysis as an exclusion criterion as no safety signals relating to renal function had been observed. The removal of this exclusion enabled an assessment of safety in a broader and more representative population of cancer subjects, e.g. inclusion of subjects with UCC
To allow for antipyretic prophylaxis with ibuprofen to be administered with two different schedules to reflect standard practice at some centres
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17 Jul 2015 |
To allow for the treatment of subjects beyond six cycles in Phase Ib of the study (in subjects not progressing by the end of Cycle 6 and in the absence of cumulative or residual toxicities Grade 2 or higher related to prior administrations of ColoAd1). The original selection of six cycles was made arbitrarily based upon previous clinical studies with cancer therapies and at the time of the amendment there was no preclinical or clinical data precluding this. A potential subject starting Cycle 6 with stable disease was also on the study at this time
To remove the mandatory requirement to treat a cohort of subjects at a dose below the recommended Phase II dose for single cycle monotherapy in the weekly schedule. This was to be performed at the discretion of the CEC
To remove the requirement for mandatory biopsies in at least two subjects in each repeat cycle schedule in Phase Ib. Biopsies proved to be a burden for subjects and as the endpoints of the study were primarily based upon safety and blood assays to compare the repeat dosing schedules it was deemed this would not affect subject safety or data integrity
A urine dipstick to detect proteinuria was introduced 24 hours before each administration of ColoAd1from Day 8 of Cycle 1 in the weekly schedule of Phase Ib following review of a DLT of nephrotic syndrome under this dosing schedule by the Clinical Events Committee and Data and Safety Monitoring Committee. In subjects with proteinuria 2+ or more, a 24 hour urine collection was included prior to the administration of ColoAd1. If proteinuria was >1 g/24 hour, administration was discussed with the Sponsor’s Medical Monitor
To introduce tumour assessment using the immune-related Response Criteria (irRC) Version 1 criteria in addition to Response Evaluation Criteria in Solid Tumours (RECIST) Version 1.1
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18 Feb 2016 |
The main reason for the amendment was to remove the restriction requiring equal numbers of subjects with urothelial cell cancer and metastatic colorectal cancer in Phase Ib per treatment schedule. This amendment was approved but no subjects were treated under this amendment as the study was terminated. Two subjects in safety follow-up after treatment discontinuation were re-consented, however no protocol specific procedures outlined in the amendment were performed.
The Medical Monitor was changed to Dr Hilary McElwaine-Johnn.
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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. | |||
| There were 9 cohorts in Phase I & 5 cohorts in Phase Ib, all with small numbers (3-9) of subjects. To aid interpretation, safety data from both phases have been integrated and reported in 3 dose groups <1x10*12, 1-3x10*12 & >3 x10*12 vp and overall. | |||
