Clinical Trial Results:
Keratinocyte Growth Factor - promoting thymic reconstitution and preventing autoimmunity after alemtuzumab (Campath-1H) treatment of multiple sclerosis. CAM-THY
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Summary
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EudraCT number |
2011-005606-30 |
Trial protocol |
GB |
Global end of trial date |
08 Aug 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
23 Aug 2018
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First version publication date |
23 Aug 2018
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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 |
CAM-THY
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01712945 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Cambridge University Hospitals NHS Foundation Trust
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Sponsor organisation address |
Hills Road, Cambridge, United Kingdom, CB2 0QQ
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Public contact |
Mrs Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, 01223 348158, carrie.bayliss@addenbrookes.nhs.uk
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Scientific contact |
Mrs Carrie Bayliss, Cambridge University Hospitals NHS Foundation Trust, 01223 348158, carrie.bayliss@addenbrookes.nhs.uk
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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 |
08 Aug 2017
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Aug 2017
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Aug 2017
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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 determine if Kepivance can prevent patients with multiple sclerosis from developing new autoimmune diseases after treatment with alemtuzumab.
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Protection of trial subjects |
All subjects received IV methylprednisolone on days 1-3 immediately prior to each cycle of alemtuzumab (given at baseline and month 12) in order to reduce infusion associated reactions. If required, subjects were also treated with antihistamines and antipyretics.
Prior to starting the study, an open label Palifermin dose escalation sub-study was performed (n=10), to determine the highest dose of Palifermin that could be tolerated by out patient group. Three dosing levels were tested - 90mcg/kg/day; 120mcg/kg/day and 180mcg/kg/day. Ten patients were enrolled into this study (signing a separate ICF). Escalation between each dosing level only occurred if no AE greater than grade 2 occurred. Following the dose escalation sub-study, 180mcg/kg/day of Palifermin was selected for the main RCT.
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Background therapy |
Alemtuzumab 12/mg per day for 5 days at baseline, and then for 3 days at month 12. IV Methylprednisolone 1/day on days 1-3 at each cycle (baseline and month 12). | ||
Evidence for comparator |
The comparator was Palifermin (Kepivance), which is recombinant human keratinocyte growth factor. Data from our group has shown that patients with the least thymic recovery of T-cells after treatment with alemtuzumab are most at risk of developing autoimmune complications. KGF has been shown in numerous animal models (murine and non-human primates) to increase thymic recovery, and in 2005 was licensed as Kepivance for use in humans to prevent mucositis induced by chemotherapy. In its pivotal licensing study, 60mcg/kg of palifermin was given for 3 days prior to conditioning, then for 3 days after shaematopoietic tem cell transplantation (HSCT). This regimen was well tolerated. Later a trial of 3 doses of palifermin (60mcg/kg) before conditioning and up to 9 doses after HSCT was shown to be safte, although it did not reduce the incidence of graft vs. host disease and did not increase lymphocyte recovery. Although thymic function was not directly studied in these patients, the results suggested that higher doses of palifermin might be required. Therefore, we designed a study to explore the tolerability of higher doses of palifermin (tested in an open-label dose escalation sub-study), then tested the efficacy of 180mcg/kg/day in a placebo-controlled "main study" aimed at testing two hypothesess (i) that palifermin increases thymic T-cell reconstitution after alemtuzumab and (ii) that in doing so reduces the risk of alemtuzumab-induced autoimmunity. A planned "stop-go" interim analysis was performed when 28 "main study" patients reached month 6. | ||
Actual start date of recruitment |
01 May 2012
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Long term follow-up planned |
Yes
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Long term follow-up rationale |
Safety | ||
Long term follow-up duration |
3 Years | ||
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 |
United Kingdom: 32
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Worldwide total number of subjects |
32
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EEA total number of subjects |
32
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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) |
32
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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 |
This was a single centre (Addenbrooke's Hospital Cambridge UK) RCT. Patient were recruited to the RCT between June 2013 and February 2015. The interim analysis was negative, so as per trial protocol recruitment halted. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Screening assessments included: EDSS, bloods (chemistry panel, full blood count, autoantibody screen, HIV, HepB and HepC), and where relevant a pregnancy test. Randomization occurred within 35 days of enrolment, or 56 days for patients who experienced a relapse or infection during screening or who required a 28 day washout of prior MS DMTs. | ||||||||||||||||||
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Period 1
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Period 1 title |
Main Study (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, Data analyst, Assessor | ||||||||||||||||||
Blinding implementation details |
Following randomisation pharmacy prepared the drug or placebo ready for preparation - both are clear colourless solutions for IV infusion, so there was no visual clue as to the identity of the IMP. Pharmacy was responsible for dispensing the trial drug based on unique randomisation codes. However, as Palifermin can cause side-effects that may compromise blinding (tongue whitening for example), all laboratory and imaging assessments were performed on link-anonymised samples in batches.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Palifermin | ||||||||||||||||||
Arm description |
Experimental group who received Palifermin | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Palifermin
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Investigational medicinal product code |
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Other name |
Kepivance, recombinant human keratinocyte growth factor
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Subjects received 180mcg/kg/day of Palifermin for 3 consecutive days immediate before and after each cycle of alemtuzumab and at months 1 and 3 after each cycle.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Control group who received placebo | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Saline
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Investigational medicinal product code |
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Other name |
Normal Saline
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Pharmaceutical forms |
Solution for injection/infusion
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Routes of administration |
Intravenous use
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Dosage and administration details |
Volume of saline to match volume of Palifermin required for 180mcg/kg/day 3 consecutive days immediate before and after each cycle of alemtuzumab and at months 1 and 3 after each cycle
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| Notes [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: As per the trial protocol the interim analysis was performed when 14 vs. 14 subjects reached month 6. Whilst the interim analysis was being performed subjects could still be recruited to the study, and 4 additional participants were (2 vs 2). Hence in total 16 participants were treated in each arm, whereas only 14 vs. 14 were included in the interim analysis. [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left. Justification: As per the trial protocol the interim analysis was performed when 14 vs. 14 subjects reached month 6. Whilst the interim analysis was being performed subjects could still be recruited to the study, and 4 additional participants were (2 vs 2). Hence in total 16 participants were treated in each arm, whereas only 14 vs. 14 were included in the interim analysis. |
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Baseline characteristics reporting groups
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Reporting group title |
Palifermin
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Reporting group description |
Experimental group who received Palifermin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Control group who received placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Palifermin Interim Group
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The interim primary endpoint (number of naive CD4+ T cells at M6) was performed when 14 vs. 14 patients reached M6 (as recruitment was allowed to continue whilst the interim analysis was performed a further 2 vs. 2 patients were recruited making the total main study number 16 vs. 16)
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Subject analysis set title |
Placebo Interim Group
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The interim primary endpoint (number of naive CD4+ T cells at M6) was performed when 14 vs. 14 patients reached M6 (as recruitment was allowed to continue whilst the interim analysis was performed a further 2 vs. 2 patients were recruited making the total main study number 16 vs. 16)
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End points reporting groups
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Reporting group title |
Palifermin
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Reporting group description |
Experimental group who received Palifermin | ||
Reporting group title |
Placebo
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Reporting group description |
Control group who received placebo | ||
Subject analysis set title |
Palifermin Interim Group
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The interim primary endpoint (number of naive CD4+ T cells at M6) was performed when 14 vs. 14 patients reached M6 (as recruitment was allowed to continue whilst the interim analysis was performed a further 2 vs. 2 patients were recruited making the total main study number 16 vs. 16)
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Subject analysis set title |
Placebo Interim Group
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
The interim primary endpoint (number of naive CD4+ T cells at M6) was performed when 14 vs. 14 patients reached M6 (as recruitment was allowed to continue whilst the interim analysis was performed a further 2 vs. 2 patients were recruited making the total main study number 16 vs. 16)
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End point title |
Autoimmunity | ||||||||||||
End point description |
For the purposes of this study secondary autoimmunity is defined as: i) the development of a novel autoimmune disease following treatment with alemtuzumab and/or ii) the generation of persistent novel autoantibodies (ANA, anti-smooth muscle, anti-TPO, and anti-mitochondrial antibodies) after treatment. Persistent is defined as present on at least 2 occasions at least 3 months apart.
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End point type |
Primary
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End point timeframe |
Month 30
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Attachments |
Untitled (Filename: Contingency of Data 1_CAMTHY_EOTD_AUTO.pdf) |
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| Notes [1] - One subject in the Placebo arm of the study was lost to follow up prior to Month 30. |
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Statistical analysis title |
Fisher Exact Test - Autoimmunity -Full data Set | ||||||||||||
Statistical analysis description |
Occurrence of autoimmunity in the Palifermin full data set vs. autoimmunity in those randomised to receive Placebo.
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Comparison groups |
Palifermin v Placebo
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Number of subjects included in analysis |
31
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.4795 [2] | ||||||||||||
Method |
Fisher exact | ||||||||||||
Confidence interval |
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| Notes [2] - Not statistically significant (but note, as recruitment to the study was halted - in keeping with the protocol following failure of the interim analysis, the trial was not powered to pick up differences in autoimmunity. |
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End point title |
Naive CD4 T cell count | ||||||||||||
End point description |
The endpoint measured was number of circulating CD4+ naive T-cells defined as CD4+ T cells that co-express CD45RA and CCR7.
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End point type |
Other pre-specified
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End point timeframe |
The interim analysis was performed when 14 vs. 14 of the main study patients reached month 6
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Attachments |
Untitled (Filename: Eudract_InterimResults.pdf) |
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Statistical analysis title |
Multivariate Linear Regression | ||||||||||||
Statistical analysis description |
The analysis estimates the the difference Placebo minus Palifermin in naive CD4 count at 6 months, adjusting for age, baseline naive CD 4 count, total palifermin dose.
The intercept represents the estimated naive CD4 T-cell count at 6 months for a 31 year old patient receiving Placebo, with a baseline CD4 T-cell count of 4 and a total Palifermin dose of 155mg (see attached document).
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Comparison groups |
Palifermin Interim Group v Placebo Interim Group
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Number of subjects included in analysis |
28
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.005 [3] | ||||||||||||
Method |
Regression, Linear | ||||||||||||
Parameter type |
Mean difference (final values) | ||||||||||||
Point estimate |
-5.132
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Confidence interval |
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95% | ||||||||||||
sides |
2-sided
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lower limit |
-8.3 | ||||||||||||
upper limit |
-1.96 | ||||||||||||
| Notes [3] - The results of this analysis demonstrated that Palifermin significant reduced naive CD4 T cell counts at month 6. |
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Adverse events information
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Timeframe for reporting adverse events |
From signing the ICF to Month 30.
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Adverse event reporting additional description |
Patients were assessed daily throughout their IMP infusions and all AEs captured. Patients were then assessed clinically every 3 months(including blood tests to screen for thyroid autoimmunity and ITP; those being the most common autoimmune complications of alemtuzumab)
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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 |
10
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Reporting groups
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Reporting group title |
Palifermin
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Reporting group description |
Experimental group who received Palifermin | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Control group who received placebo | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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23 May 2012 |
To allow advertising on our group website |
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20 Aug 2012 |
1. Change of inclusion criterion - initially the inclusion criteria included selecting patients based on high serum IL-21 (in order to try and select patients most at risk of developing autoimmunity). In this amendment this was changed to selecting patients on low IL-7 for the same reasons; changed because of poor reproducibality in commercially available IL-21 ELISA assay kit. Please note this amendment occurred well before patients were selected for involvement in the main, randomized control trial part of the study, whilst we were recruiting patients to the open label dose escalation part of the study.
2. To remove advice regarding yearly pap smears (no longer advised by DOH)
3. To clarify preparation of alemtuzumab |
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26 Nov 2012 |
1. Legal status of alemtuzumab amended following withdrawal of MA by Genzyme in August 2012.
2. Clarification of statistical operational analysis
3. Correction of minor typographical error |
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20 May 2013 |
1. Change of CI from Prof Alasdair Coles to Dr Joanne Jones.
2. To refine the definition of secondary autoimmunity to include novel autoantibodies after alemtuzumab (namely ANA, anti-smooth muscle, anti-TPO, and anti-mitochondrial antibodies) present on at least 2 occasions and detected at least 3 months apart.
3. To remove IL-7 from inclusion criteria
4. To measure anti-nuclear, smooth muscle, mitochondrial and TPO antibodies pre and 3 monthly following alemtuzumab.
5. The addition of an interim analysis statistician and temporary member of the independent trial steering committee for futility analysis
Please note this amendment occurred before patients were selected for involvement in the main, randomized control trial part of the study, whilst we were recruiting patients to the open label dose escalation part of the study. |
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01 Oct 2013 |
1. To change the formulation of IMP from Alemtuzumab 30mg/mL to Alemtuzumab 10mg/mL (either supplied as unlicensed drug, or Lemtrada )
3. To update the Legal status of alemtuzumab (to reflect new MA of alemtuzumab as Lemtrada as a treatment for relapsing remitting MS).
4. To modify the rules around repeat FBC testing following a platelet count below the LLN but >100 - in order to prevent unnecessary repeat testing for individuals whose platelet counts dipped just below the low limit of normal.
5. To correct an omission of baseline autoantibodies from the trial synopsis
6. To update the adverse effects seen following administration of Kepivance (PIS change only) - in order to inform potential participants of the range of AEs we had seen in the dose escalation phase of the study.
This was the only amendment to occur during recruitment of individuals to the main/RCT part of the study. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| The interim milestone (14 vs. 14 patients at M6) was not passed so as per protocol recruitment to the trial was stopped. Therefore although the trial has clearly shown that Palifermin reduces thympopoesis, it is underpowered to assess autoimmunity. | |||
